In 2011, Traish et al. determined the possibility of a causal relationship between 5a-reductase inhibitor use and persistent sexual dysfunction in a subset of consumers. They reported the case of a young man who suffered significant sexual dysfunction, libido loss and a depressive symptomatology that continued 11 years after only weeks of exposure to finasteride for AGA (Traish et al., 2011). Irwig and Kolukula first characterised persistent sexual dysfunction in 71 otherwise healthy men who had used finasteride for AGA. 94% experienced low libido, 92% had erectile dysfunction, 92% developed decreased arousal, and 69% developed orgasm dysfunction. Compared with before use, mean sexual episodes per month dropped and sexual dysfunction score per Arizona Sexual Experience Scale increased (P < 0.0001) (Irwig & Kolukula, 2011). In a follow up report, 54 of these men were reassessed at a mean of 14 months following their initial interview dates. The mean age of the patients was 31 years and the mean age at assumption of finasteride was 26 years, with a mean duration of 23 months of use. Participants had no baseline sexual dysfunction or psychiatric conditions before use of finasteride. Persistent sexual side effects continued to be present in 96%. 89% of subjects continued to meet the definition of sexual dysfunction according to ASEX. Mean (± SD) total scores were 7.2±2.0 before finasteride, 22.2±2.6 after finasteride at the time of the interview, and 20.8±3.6 at reassessment. Severity of sexual dysfunction did not correlate to duration of finasteride use or duration of persistent effects. Irwig noted a broad range of commonly reported persistent effects beyond those formally assessed by the ASEX including decreased volume of ejaculate, loss of penile size and/or testicular size, testicular pain, prostatitis, penile curvature, reduced penile sensation, a reduction in spontaneous erections. Additionally, subjects reported difficulty sleeping, mental impairment, and depressive symptoms (Irwig, 2012b).
In a group of 61 PFS subjects who completed the BDI-II, rates of depressive symptoms were markedly higher (75%) than the control group (10%). While 3% of controls reported suicidal thoughts, this was significantly more frequent in PFS patients. 39% of PFS patients exhibited suicidality with 5% having chosen the statement “I would like to kill myself”. Mean (± SD) scores from the 21-item BDI-II were 23.67 (± 12.56) in PFS patients and 5.93 (± 4.48) in the control group (P < .0001) (Irwig, 2012a). Irwig additionally reported a decrease in alcohol consumption in a cohort of 63 PFS patients compared to before use of finasteride. Mean alcoholic beverages consumed per week declined from 5.2±0.7 before finasteride to 2.0±0.3 after finasteride (p < 0.0001), consistent with observations regarding finasteride’s attenuation of alcohol consumption in animal experiments (Irwig, 2013). Reporting androgen levels and semen parameters in 24 PFS patients, 13% were found to have low total testosterone and 13% had low serum DHT, however mean levels were close to other studies and could not explain the persistent symptoms. 16% (3 of 19) had severe oligospermia, whereas this finding would be expected in 3% of fertile-age men (Irwig, 2014). Considering the medical records of 6 men who committed suicide following use and cessation of finasteride, Irwig noted common symptoms of persistent sexual dysfunction and insomnia across all cases (Irwig, 2020).
Drasa et al. enrolled 35 patients with persistent sexual and nonsexual symptoms following use and cessation of finasteride for male pattern hair loss. Patients had an average age of 30 and mean use of finasteride was 24 months. Assessment was a mean of 12 months after discontinuation. ASEX completion with respect to before and after use of finasteride showed a mean increase of 14.75. 59% of patients experienced severe symptoms per the AMS. 68% of participants reported a worsening after cessation of the drug, and a trend of symptomatic worsening over the course of their condition was reported by 63%. Duration of use and symptom severity were not statistically associated (Drasa, 2014).
Ganzer et al. reported a characterisation of the persistent physical, psychological, and cognitive symptoms experienced by PFS patients who had used the drug for at least 3 months and experienced health problems after cessation of finasteride. The authors constructed a web-based questionnaire including ad-hoc questions based around a symptom profile generated from literature review and 100 private patients’ reports to the author’s practice. Demographic characteristics, data regarding use and cessation of the drug, and the onset of symptoms were also ascertained. Additionally, men were questioned as to the medical support they had sought and their satisfaction with their clinical assessment and treatments. 100 patients who had sought medical assistance were invited by email and additional patients were recruited from propeciahelp.com. No participant had a pre-existing sexual dysfunction or psychiatric condition. 93% reported having used the 1mg finasteride preparation. 84% of patients reported that they were asymptomatic during use of the medication and symptom onset began after cessation, rapidly so in 68% of patients. Respondents reported experiencing physical symptoms of fatigue (69%), muscle atrophy and weakness (56%), fasciculations (47%), decreased oil and sebum (41%), dry and thinned skin (68%), metabolic changes and increased fat deposition (54%). 14% of respondents reported a finding of raised fasting glucose and triglycerides. Sexual dysfunction included diminished libido (93%), loss of spontaneous and morning erections (89%), complete impotence (40%), reduced semen volume and ejaculatory force (82%), orgasm dysfunction (40%) and sexual anhedonia (70%). Penile atrophy (79%) scrotal atrophy (51%) and sensory changes were reported. 20% reported Peyronie’s disease. Cognitive complaints were highly prevalent, including severe memory impairment (56%), mental cloudiness or brain fog (75%), impaired problem solving (69%) and attentional deficits (74%). Chronic insomnia was reported by 58% of men. Nearly three quarters of respondents reported increased anxiety, low mood, and anhedonia. Of concern, 63% of respondents had suicidal ideation and felt they could not keep living on with their extreme side effects. In terms of medical support, 50% had initially consulted a urologist while 62% saw their primary care provider. Physicians generally attributed physical symptoms to being of a psychological nature and recommended psychiatric consultation (69%). 93% of men were frustrated by clinical ignorance, inadequate recognition of the validity of their symptoms, and were dissatisfied with the medical care that they received. The authors conclude the aggregate multi-domain symptom profile could constitute a definable syndrome (Ganzer et al., 2014).
Chiriacò et al. conducted a similar retrospective evaluation. 79 men who had used finasteride for AGA and experienced persistent symptoms for a minimum of six months were asked to answer 100 ad-hoc questions, both a pre and post-finasteride ASEX questionnaire, and the Aging Male Symptom Scale (AMS) questionnaire. Mean age of participants was 33. Finasteride had been taken for an average of approximately 2 years. All subjects were still symptomatic at assessment. 89.9% of participants noticed some symptoms during finasteride use, and the trend of symptoms after discontinuation was worsening in 62% of patients, with a trend of improvement reported in 13.9%. Sexual symptoms included loss of penile sensitivity (87.3%), decreased ejaculatory force (82.3%), decreased penile temperature (78.5%), reduced ejaculate volume (73.4%), reduction in penile dimension (65.8%), perineal tightness (45.6%). Other symptoms included anhedonia (75.9%), concentration problems (72.2%), loss of muscle tone and mass (51.9%), and increased body weight (48.1%). Post-finasteride ASEX score ranged from 13–30 (21.0 ± 2.67), with 78.5% having ASEX ≥19 points indicating sexual dysfunction. This included 44.3% of patients indicating severe difficulty or incapability of getting/keeping an erection. Pre-finasteride ASEX score was far lower (p < 0.001) ranging 5–15 (7.7 ± 2.52), indicating no overt sexual dysfunction. Of 78 patients with available data, all had some signs of androgen deficiency per the AMS, with 60.3% with an AMS score of ≥50 points indicating severe deficiency. The authors note the reports by their PFS patients suggest androgen deficiency across different tissues where 5alpha reductase is expressed at an average of four years after finasteride discontinuation, indicating that permanent changes occurred in the human body (Chiriacò et al., 2016).
Walf et al. sought to characterise persistent symptoms following finasteride treatment and its discontinuation by assessment of subjective patient reports on propeciahelp.com. 244 cases were isolated from discussions in a discrete time period. Walf et al. placed symptoms into four broad categories: Antiandrogenic effects, estrogenic effects, central effects and nonspecific adverse effects. Antiandrogenic adverse effects were described to be genital dysfunction, testicular dysfunction and infertility, accessory sexual or genitourinary organ dysfunction, psychosexual function, and hormonal function. Estrogenic AEs included breast cancer, breast neoplasm or breast mass, gynecomastia, breast pain, and increased serum estrogen. Central effects involved depression, anxiety, confusion and “brain fog”, insomnia and attentional difficulties. The nonspecific/severe AEs were defined as muscle twitching, lower back pain, weight gain, fatigue, numbness in the anal region, muscle spasms, excessive sweating, bleeding gums, tinnitus, hot flashes, irregular stool, scoliosis, and discoloration of the urine. While these presented heterogeneously, some individuals experienced adverse events across all categories (Walf et al., 2018).
In a retrospective control matched study, Di Loreto et al. evaluated expression of the androgen receptor and nerve density in multiple cell lines of prepuce tissue in PFS patients aged 29–43 years who had experienced persistent sexual symptoms for over 6 months, with the notable finding of persistent androgen receptor overexpression (Di Loreto et al., 2014). Patients had used finasteride for an average of 32 months and had stopped using an average of 56 months to the point of study, at which point all patients remained symptomatic. PFS patients self-reported symptoms including loss of penile sensation, erectile dysfunction, pain in the penis, scrotum or testes, penile tissue changes, reduced penile dimensions, and reduced volume of ejaculate. PFS cases experienced sexual dysfunction at point of interview per Arizona Sexual Experience Scale (22.5±2.78). PFS patients were additionally asked to complete the ASEX survey considering themselves before use of finasteride and these pre-finasteride scores indicated no pre-existing sexual dysfunction (7.6±1.92). Histological evaluation of nerve density revealed similarity with controls. Immunohistochemistry revealed a significantly higher percentage of nuclear AR-positive epithelial cells in all cases (mean±SD, 80.6±8.63%) than in controls (mean±SD, 65.0±19.1%), P = 0.043. Stromal cells in all cases showed a significantly greater expression of AR in the nuclei compared to controls (mean±SD, 40.0±15.1% in cases versus 23.4±8.68% in controls), P = 0.023. Percentage of AR positive vessel smooth muscle cells did not differ significantly between the 2 groups. Averagely, AR positive cells in the 3 tissues was higher in cases than in controls. Di Loreto et al. speculate that the ostensibly permanent effects could be due to mechanisms of ageing prematurely induced by artificially reduced androgen levels with finasteride. They conclude a better understanding of the molecular events may inform possible therapies for these severe effects in young men of fertile age (Di Loreto et al., 2014). Although unreported in the manuscript, La Marra, co-author of the study, further elaborated on the data in a thesis centring on the investigation. He reported the percentages of AR positive cells are always higher in the cases than in the controls. He further reported positive correlations between the increase of AR levels in the epithelial and stromal cells and the decrease in ability/frequency to perform sexually per the AMS, the increase of AR in the vessels cells and the intensification of ASEX sexual dysfunction and physical exhaustion, and the increase of AR in the epithelial cells and the worsening of muscular weakness and feeling “burnt out” per AMS. La Marra noted that exogenous androgens do little to improve – and sometimes worsen – PFS symptoms, concluding that investigations should centre on epigenetic alterations relevant to the changed sensitivity of the AR (La Marra, 2010). Di Loreto’s investigation was the first to report significant objective differences at the molecular level and it has subsequently been suggested that local AR levels could play a pathological role in PFS (Than et al., 2018; Traish, 2018).
Demonstrating multisystem involvement in absence of what the authors regarded to be the “typical” neurological and sexual complaints, Gupta et al. reported a 33 year old man with PFS who suffered itching, burning micturition, abdominal discomfort, skin rash, and seborrhoea after a first use of 0.5mg dutasteride for a month. These symptoms subsided with the adoption of exercise but had reoccurred and persisted after attempting AGA therapy with finasteride 1mg four years later. Keratotic follicular papules and pustules were apparent on his shoulders and back. Semen analysis revealed pus cells and moderate growth of Enterococcus faecalis following culture. Therapeutic attempts over the following years at three centres were not successful (Sharma et al., 2016). Motofei also reported an uncommon presentation in a 52 year old who presented with generalised vitiligo 2 months after cessation alongside symptoms including bilateral gynecomastia, sexual dysfunction and depression that were not present upon pre-treatment evaluation (Motofei et al., 2017).
Cecchin et al. reported a significantly higher occurrence of “extreme length” AR polymorphisms (CAG-rs4045402 and GGN-rs3138869) in PFS patients following finasteride use for AGA as compared to controls without AGA, suggestive of a potential genetic role in the development of AGA and PFS (Cecchin et al., 2014). Cauci et al. expanded on this in a subsequent study exploring the relationship of AR polyglutamine stretch-encoding (CAG) and polyglycine stretch-encoding (GGN) polymorphisms with the individual symptoms of PFS in 66 patients experiencing symptoms for a median of three years after cessation. Patients were asked to describe their trend of symptoms after discontinuation (improved, unchanged or worsening). 57.6% of PFS patients responded that their trend after was worsening. Androgen receptor polymorphisms were correlated to the frequency of several PFS symptoms. Patients completed a bespoke symptom questionnaire in addition to the ASEX and the AMS. While total scores of the ASEX and AMS did not differ with length of (CAG)n and (GGN)n repeats, significant differences were found within individual PFS symptoms. Patients with shorter CAG repeat lengths (9-19) used finasteride for a shorter time than those with medium (20-24) or long (≥25) repeat lengths, and 83.3% of this short CAGn group reported severe libido loss, scoring 5 on item 17 of the AMS. Increased body weight (>2kg) following use of finasteride was most associated with those with long CAG repeats. Interestingly, skin dryness showed a parabolic curvilinear profile, with short and long CAGn groups having higher frequencies (50% and 63.6% respectively) than the medium CAGn group (18.9%). Muscle spasms were found to be more frequent amongst long CAGn carriers (72.7%). Patients with long (>23) GGN repeats did not report experiencing scrotal pain compared with 34.1% of those with medium (23) GGN repeats and 32.7% of those with medium to short length (≤23) repeats. Penile pain was likewise more often seen in those with short or medium rather than long GGN repeats (34.6% vs 7.1%). Long GGN repeats were also associated with a better phenotype regarding fatigue, loss of vitality, depression and the feeling of passing one’s peak than those with medium repeats. Loss of perineal fullness was reported by 100% of men with short GGNn repeat lengths, 70.5% of men with medium GGN repeats and 57.1% of those with long repeats. The results of Cauci et al. suggest genetic involvement in the symptom profile of PFS, and the authors conclude the need for much more research into the pathophysiology, particularly with a precision medicine approach (Cauci et al., 2017).
In a clinical assessment of 24 PFS patients, Basaria et al. found no significant sequence variations in AR, SRD5A1 or SRD5A2. Depression scores were significantly higher in PFS patients via BDI, Hamilton Depression inventory and PHQ-9. PHQ-9 scoring was not significantly related to either the duration of finasteride use or the time since discontinuation of the drug. Some characteristics were measured and were not significantly different to controls. No hormonal correlate able to account for the pathological presentation was identified. Two fMRI measurements suggested neurobiological abnormalities PFS patients. fMRI of PFS patients’ brains in response to erotic stimuli was conducted. Worsening IIEF scores correlated to increased activity in the neural areas the authors deemed to correspond with sexual arousal, while activity in brain regions associated with higher level cognitive and motivational networks decreased concomitantly, revealing a dissociation in activity that may be a marker of neural changes following use of finasteride. Blood-oxygen dependent activity in brain areas implicated in major depression were also identified in PFS patients with correlation to BDI scores pertaining to negative affect (Basaria et al., 2016). This study included limited gene expression assay of skin taken from the back of symptomatic patients and non-symptomatic finasteride users. Although the paper stated that “we did not find evidence of…significant alterations in expression of AR-dependent genes in the skin”, this is not completely reflective of the statement in the study’s supplementary appendix: “While the DESeq analysis determined there were statistically significant differences in a few of the androgen-regulated genes, the hierarchical clustering analysis revealed that the symptomatic and non-symptomatic subjects did not share the immediate cluster” (Basaria et al., 2016 appendix: methods).
Melcangi et al. Performed case-controlled clinical evaluations of 16 PFS patients aged 22-44 with a strong focus on the neurological presentation of the syndrome. Mean treatment duration was 1037 days with a range of 451–4697 days between cessation of finasteride and clinical evaluation. 50% of PFS patients were deemed to suffer from major depressive disorder per screening with the Mini-International Neuropsychiatric Interview, and scores of Beck Depression Inventory and Beck Anxiety Inventory were significantly higher in those with MDD. Ten patients experienced severe ED per the IIEF15, while the remaining 6 exhibited mild to moderate ED. Ultrasound determination of testicular volume was calculated to be normal in patients. Objective markers of neuropathy were determined in 25% of patients via sensory evoked potentials of the pudendal nerve, while 75% of the patients had normal PN_SEPs. No evidence of metabolic, toxic, or inherited disease associated with peripheral nervous system damage was detected. Interestingly, depression scores were not correlated to PN_SEPs while sexual dysfunction scores were. The cerebrospinal fluid of 14 patients was analysed with comparison to 25 healthy age-matched controls. Significant differences were determined. Pregnenolone, isopregnanolone, progesterone and dihydroprogesterone were significantly decreased, while levels of dehydroepiandrosterone (DHEA), testosterone and 3α-diol were increased. Additionally, 17β-estradiol and DHT were decreased. Plasma determination showed differences to the CSF findings. In serum, pregnenolone, tetrahydroprogesterone, DHEA and T were significantly increased, while dihydroprogesterone was significantly decreased (Melcangi et al., 2017). This disruption in neurosteroids is notedly heterogenous and differed slightly to findings from their previous pilot study involving 3 PFS patients (Melcangi et al., 2013). Melcangi et al. later reported that the gene promoter of SRD5A2 was methylated in CSF samples of 9 of 16 PFS patients (age 34.5 ± 8.8 years) compared with 1 of 13 age-matched controls. Interestingly, the single control with SRD5A2 methylation had a diagnosis of normotensive hydrocephalus. Amongst PFS patients the methylation ranged from 15.4 to 100%. Neither depression, anxiety or erectile dysfunction scoring via validated scales were correlated to methylation status. Methylation was not found in blood DNA, demonstrating tissue specificity. SRD5A1 was found to be unmethylated across samples and groups (Melcangi et al., 2019).
Rubin et al. Performed penile duplex Doppler ultrasound examination with a high frequency probe during maximal pharmacologic erection on 27 PFS patients. Patients had a mean age of 31, no known cardiovascular risk factors, and had sexual dysfunction following use of finasteride. 26 of 27 patients (96%) demonstrated lack of homogeneity and hyperechoic/hypoechoic regions in erectile tissue. They concluded induced corporal smooth muscle apoptosis and fibrosis may represent a biologic pathophysiology responsible for impairing tissue expandability resulted in venoocclusive dysfunction and ED (Rubin et al., 2018). Mirabal et al. issued 25 patients with persistent symptoms following 5ari use for AGA and 25 controls a range of validated questionnaires related to self-reported symptomatology including the IIEF, the International Prostate Symptom Score (IPSS), the Patient Health Questionnaire-9 (PHQ-9) and the Androgen Deficiency in the Aging Male (ADAM). Post-5ari patients had significantly higher median scores compared with controls in the IIEF (35 vs 29, p=0.035), the IPSS (10 vs 3, p < 0.01), the PHQ-9 (10 vs 1, p < 0.001), and had significant differences in all questions of the ADAM. Penile duplex doppler ultrasound revealed vascular abnormalities in 17 (68%) post-5ari patients. Alarmingly, 2 (8%) of post-5ari patients committed suicide during and after the study. Mirabal et al. concluded that there may be persistent genitourinary, physical, psycho-cognitive, anti-androgenic and penile vascular changes after 5ARI discontinuation in addition to persistent sexual dysfunction (Mirabal, 2019).
Epidemiological research into PFS has thus far been limited to sexual dysfunction and depressive symptoms. Ali et al. used data mining techniques with FAERS data to conduct a retrospective pharmacovigilance disproportionality analysis. They analysed reports of sexual dysfunction and suicidal ideation between 1998 and 2013 in men aged 18-45 who had used low-dose finasteride. Supportive of survey research previously discussed, the data revealed that a strong signal of persistent sexual dysfunction and disproportional reporting of suicidal ideation. Most sexual dysfunction reports were serious, with 43.5% resulting in disability. 87% of incidences of suicidal ideation occurred in men also experiencing sexual dysfunction from low-dose finasteride. Most of these events were classed as serious (e.g., contributed to the patient’s death, hospitalization, or disability). Ali note there is mechanistic plausibility in the link between finasteride and the risks of sexual dysfunction and suicidal ideation, and that the disproportional reporting could be symptoms of Post-Finasteride Syndrome. The authors conclude that, although a causal link cannot be inferred from this study due to the nature of the data, young men receiving low-dose finasteride for AGA are at risk of persistent sexual dysfunction that may lead to suicidal ideation (Ali et al., 2015).
Kiguradze et al. have provided a well-designed analysis of a large set of data from the Northwestern Medicine Enterprise Data Warehouse with sole regards to persistent erectile dysfunction following use of finasteride or dutasteride. They conclusively identified a strong and intrinsic association between debilitating persistent sexual dysfunction and exposure to low dose finasteride or dutasteride. Duration of 5-alpha reductase inhibitor exposure was a greater predictive risk factor for ED in young men than all other assessed factors. Of 4,284 young men, without prior sexual dysfunction, taking finasteride at a dose less than 1.25 mg/day, 34 (0.79%) developed persistent erectile dysfunction with a median 1,534 days after drug cessation (interquartile range of 651–2,351 days). Of 103 young men with new ED, 34 (33%) had new persistent erectile dysfunction (Kiguradze et al., 2017).
Through obtaining finasteride-related adverse events catalogued by the FAERS reporting system between April 2011 and October 2014, Fiuk et al. identified 105 women with finasteride-associated adverse events following use. These included typical PFS symptoms including dry eyes, sleep disturbances and suicidal ideation as well as hearing loss, renal failure, urosepsis, new incidences of breast cancer, haemorrhagic diathesis. They concluded female PFS patients represent a small but real subset of long term finasteride-related adverse events, and that further etiological investigation of this devastating syndrome is crucial (Fiuk et al., 2016).
In addition to the significant primary findings in PFS patients discussed, the subject is far more regularly the focus of literature review. Than et al. concluded that the existing evidence well supports the existence of persistent sexual, physical, neurological and central effects following 5alpha reductase inhibitor exposure, and that a growing understanding of the constellation of symptoms describing PFS can inform prescribing clinicians as to the risk and benefit of prescription (Than et al., 2018). Traish considered that the magnitude of the broad and serious symptomatology of the syndrome is inadequately appreciated. Persistent loss of libido and erectile dysfunction are recognised to be serious issues pertaining to quality of life and wellbeing, as well as “signs of something terribly amiss with physiological process”. Traish further deemed it imperative that the scientific and medical communities act now to seek a better understanding the pathophysiology of this serious and debilitating disorder, expand awareness amongst physicians and patients, and develop tools for treatment (Traish, 2018). Said and Mehta concluded that comprehensive literature review shows a disproportionately high number of men with 5-α reductase inhibitor-associated sexual dysfunction and infertility, and that though uncommon, broad sexual and reproductive symptoms that are both serious and persistent can occur. They note that while methodological concerns have been raised regarding the possibilities of recall and selection bias in the questionnaire-based study of PFS patients, their results parallel scientific observations about the long-term pathophysiological changes induced by finasteride, even after treatment discontinuation. They suggest physicians engage in productive conversation regarding the potential impact of these medications on their health and quality of life before 5alpha reductase inhibitor prescription (Said & Mehta, 2018).
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