Post-Finasteride Syndrome, what makes it novel and

Post-Finasteride Syndrome

Post-Finasteride Syndrome is a life-altering disease occurring rarely following therapeutic use of a 5-alpha reductase inhibitor such as Finasteride. PFS encompasses serious physical, neurological, and sexual symptoms of variable severity and distribution. Duration of use is not positively correlated with the severity or persistence of the symptoms of PFS, and although the condition can develop rapidly after many years of asymptomatic use, severely affected phenotypes can follow as little as one dose ​(Garreton et al., 2016; Than et al., 2018)​. The condition is currently without known predictive factors, disease-modifying treatment or effective therapeutic relief, and thus represents a serious and increasingly urgent unrecognised public health risk as online marketing for finasteride increases.

The diverse symptoms of PFS and their potential severity are not adequately appreciated by clinicians nor in medical literature ​(Traish, 2018)​. PFS presents heterogeneously, with variably severe symptoms from a broad constellation, in isolation or combination. Despite the significant interindividual differences in presentation, there are key commonalities in the disease behaviour. The health of the most severely affected patients is so profoundly impacted that they cannot continue their lives in a meaningful capacity. PFS is frequently causative of relationship breakdown, disability preventing work, isolation and suicide. Although of controversial practical application, Maslow’s hierarchy of needs is a pervasive categorisation of motivating human needs ​(Kenrick et al., 2010)​. PFS, by this measure, can prove ruinous to the attainment of basic physiological needs in sleep and sex, safety needs in emotional security, financial security and health, and the interpersonal needs of friendships, intimacy and family.

Symptoms of PFS

Sexual dysfunction, including:

  • Erectile Dysfunction
  • Loss of libido
  • Ejaculatory and orgasm disorders
  • Clear, watery ejaculate
  • Genital anaesthesia
  • Post-orgasm exacerbation of symptoms

Symptoms of androgen-responsive tissue, including:

  • Atrophy of penile tissue and penile deformation
  • Venous leak, penile calcification, penile fibrosis
  • Penile, testicular, perineal and prostate pain
  • Testicular atrophy
  • Muscle atrophy
  • Muscular dysfunction, fasciculations, tremors
  • Dry eyes
  • Osteopenia, osteoporosis
  • Tooth decay and tooth loss
  • Skin pigmentation changes including darkened penile skin
  • Thinned skin
  • Dry skin
  • Acceleration or deceleration of male pattern hair loss

Other physiological changes, including:

  • Lessened beard growth and altered pigmentation
  • Altered body temperature
  • Gynecomastia
  • Changes in fat distribution; Increased gynoid and android fat
  • Alteration in allergic reactions

Neurological and Cognitive dysfunction, including:

  • Depression, Anhedonia
  • Memory failure (short term and long term)
  • Cognitive impairment
  • Anxiety and panic attacks
  • Insomnia

Autonomic and sensory nervous system and somatic symptoms, including:

  • Sinus arrhythmia, bradycardia, tachycardia
  • Sleep apnoea (obstructive, central)
  • Visual impairment and problems including visual snow
  • Head pressure, vertigo and dizziness
  • hearing difficulty and tinnitus
  • Digestive impairment including dysmotility, pale stools, diarrhoea and constipation
  • Numbness, tingling or stinging/burning sensations, often in distal extremities

Endocrine and metabolic alterations can include:

  • Alteration in serum hormonal parameters including T, E, LH
  • Deregulation between LH and T
  • Low vitamin D3
  • Increased triglycerides
  • Increased creatine kinase
  • Metabolic dysfunction, Insulin resistance, glucose intolerance
  • Hyperbilirubinemia
  • Decreased 3a-diol-G
  • Lowered CSF neurosteroids

What makes PFS novel?

  • Persistent and frequently permanent.
  • Interindividually variable improvement or deterioration over course of disease progression.
  • Disease ordinarily progresses in absence of the drug: Majority of cases involve rapid progressive onset or intensification of health problems that patients colloquially refer to as a “crash” after cessation of drug.
  • Heterogenous presentation: Differing symptoms and severities across patients with variable site-specific involvement.
  • Severity is not positively correlated to length of exposure; severe multisystemically affected phenotypes occur after less than 1mg total.
  • Atypical spatiotemporal involvement: More common in younger men taking lower dose for hair loss than older men using for BPH. Associated with greater disability in young men (FAERS data).
  • Consequential endocrine fragility: Despite a frequent and curious symptomatic relief, severely affected patients liable to permanent phenotypical worsening following exposure to substances with antiandrogenic properties.

Characteristics inadequately explored in medical literature add significantly to the understanding of the condition and its peculiarity. While PFS is frequently mischaracterised as persistent side effects, in a majority of cases PFS involves the onset or intensification of health problems after cessation of the drug. This counter-intuitive phenomenon, which is often sudden and debilitating, is colloquially referred to as the “crash” by patients. Often, this follows a partial or sometimes even complete resolution of any side effects experienced on the drug. This is a remarkable and intrinsic novel characteristic so frequent that media coverage of the condition expresses awareness of the phenomenon ​(Morgans, 2018)​. The majority of PFS patients are younger men who have taken Finasteride 1mg, or a division of the 1mg or 5mg tablets, for treatment of AGA. This is represented in Adverse Drug Reaction (ADR) reports to the FDA FAERS scheme. FAERS data shows a markedly higher number of adverse event reports from this group, coherent with a higher incidence of associated disability ​(Baas et al., 2018)​. This is notably atypical in that ADRs are usually more common and severe in aged populations ​(Lavan & Gallagher, 2015)​. As finasteride is widely prescribed and PFS is proportionally very rare, there is likely to be a predisposition in consumers who develop PFS. The apparent prevalence in younger individuals, as well as reports of rapid development of the condition upon later rechallenge in previously asymptomatic or mildly symptomatic users further suggests the involvement of spatiotemporal factors, perhaps at the level of gene expression.

PFS is without a consistent biomarker, however patients with prior hormonal bloodwork will often report significant alterations to their serum hormonal profile following onset of the condition, including raised or reduced testosterone. Low luteinising hormone values is commonly reported. Additionally, low vitamin D and signs of metabolic alteration including increased triglycerides and elevated bilirubin can be frequently apparent. Basic urological evaluation may be subclinical or unrevealing, but this is not always the case and clinical evaluation of PFS patients describing a severe or total sexual dysfunction and penile changes who are clinically examined regularly receive relevant diagnoses including penile venous leak, microcalcifications, fibrosis and markers of neuropathy. These outcomes, are not dose dependent, often developing and progressing rapidly after cessation in severely affected patients who took only a single dose. Professor Daniel Stewart, a previously healthy man with no pre-existing mental or sexual dysfunction, developed PFS severely following little over one week of 1mg Finasteride. After cessation due to side effects he experienced the crash, developing sexual dysfunction, genital pain and atrophy, severe muscle atrophy, weight loss, extreme fatigue, cognitive dysfunction, anxiety and insomnia. Daniel committed suicide at age 37 after suffering for eight months, writing to his family that “Finasteride has destroyed my mind and body”. He had received a diagnosis of penile venous leakage ​(PFS Foundation, 2017)​.

Appreciation of PFS has often entailed a narrow clinical focus, and the reality is alarming drug-induced health problems that extend far beyond erectile dysfunction and depression. Given the diverse array of symptoms and lack of interdependence, it is in our view highly likely many consumers will have developed health problems they have failed to associate with the causative product due to the potential for insidious onset and counter-intuitive presentation after withdrawal. As of 2020, many symptoms are recorded in some capacity in medical literature, however the breadth is only apparent upon comprehensive review. Clinical characterisation of PFS in literature review is often incomplete and can be highly selective in line with the specialisation or hypotheses of the authors. The clear establishment of the multidomain symptom profile is therefore of paramount importance in line with increasing commentaries on the condition.

Originating in 2003, propeciahelp is the largest and longest running website for patients suffering from persistent sexual, neurological and physiological side effects arising following use of the drug Finasteride (branded Propecia). aims to provide a place of discussion for those affected by PFS. Propeciahelp’s discussion forum is a vast record of PFS patient experiences and has been considered a source of clinical information ​(Diviccaro et al., 2020)​. Although the quality of discussion is variable, patient posts which provide clear accounts of individual symptoms, the manner of onset and disease progression are of clinical value. Submissions have been the subject of published attempts at recording and categorising the multi-system symptom profile ​(Walf et al., 2018)​.

In the absence of adequate clinical education regarding PFS, propeciahelp remains a key support to many patients. Along with the families of PFS patients who were driven to suicide by their symptoms, the administrative staff of propeciahelp assisted in the formation of the PFS foundation which has funded scientific research into the condition through charitable donations. To deliver a structured clinical characterisation of the condition, propeciahelp launched a comprehensive Post-Drug Syndrome Survey in March 2019 and recently passed 200 submissions from post-Finasteride patients experiencing persistent symptoms for a minimum of three months following cessation. We will seek to publish detailed results in the future.

As well as having designed and gathered the largest standardised self-reported dataset concerning PFS, over a decade operating the largest patient support website provides us with a unique insight into the clinical situation. The administrators of propeciahelp have herein summarised current research on PFS. We additionally present a contextual mechanistic hypothesis as basis for future investigation. The vital role of the AR in physiological domains relevant to the symptomatology of PFS is reviewed. This document is intended to aid those with scientific interest in understanding the condition and the practical expertise to uncover the molecular mechanisms underlying this remarkable disease.

Page Bibliography

  1. Baas, W. R., Butcher, M. J., Lwin, A., Holland, B., Herberts, M., Clemons, J., Delfino, K., Althof, S., Kohler, T. S., & McVary, K. T. (2018). A Review of the FAERS Data on 5-Alpha Reductase Inhibitors: Implications for Postfinasteride Syndrome. Urology, 143–149.
  2. Diviccaro, S., Melcangi, R. C., & Giatti, S. (2020). Post-finasteride syndrome: An emerging clinical problem. Neurobiology of Stress, 100209.
  3. Garreton, A. S., Valzacchi, G. R., & Layus, O. (2016). Post-Finasteride Syndrome: About 2 Cases and Review of the Literature. Andrology-Open Access.
  4. Kenrick, D. T., Griskevicius, V., Neuberg, S. L., & Schaller, M. (2010). Renovating the Pyramid of Needs. Perspectives on Psychological Science, 292–314.
  5. Lavan, A. H., & Gallagher, P. (2015). Predicting risk of adverse drug reactions in older adults. Therapeutic Advances in Drug Safety, 11–22.
  6. Morgans, J. (2018, April 24). I Need to Quit Hair Loss Drugs Before They Kill Me. Vice.
  7. PFS Foundation. (2017). PFS Foundation citizen’s petition. FDA-2017-P-5787, Request FDA require the immediate removal of Propecia (and generic formulations of finasteride, 1 mg, for androgenic alopecia) from the market. Regulations.Gov.
  8. Than, J. K., Rodriguez, K., & Khera, M. (2018). Post-finasteride Syndrome: A Review of Current Literature. Current Sexual Health Reports, 152–157.
  9. Traish, A. M. (2018). The Post-finasteride Syndrome: Clinical Manifestation of Drug-Induced Epigenetics Due to Endocrine Disruption. Current Sexual Health Reports, 88–103.
  10. Walf, A. A., Kaurejo, S., & Frye, C. A. (2018). Research Brief: Self-Reports of a Constellation of Persistent Antiandrogenic, Estrogenic, Physical, and Psychological Effects of Finasteride Usage Among Men. American Journal of Men’s Health, 900–906.