Research going forward

The clinical picture and molecular level understanding of PFS are not where they should be after decades of clear reports of profound suffering and suicides caused by exposure to a cosmetic product. Understanding of a disease, its basic molecular mechanisms, accurate experimental models with predictive value of the disease, and access to technologies for target validation are important for progress towards a therapy ​(Gashaw et al., 2011)​ and we urge immediate steps to these ends. Finasteride is a potent endocrine disruptor that targets diverse tissues across the organism. The severity of the symptoms must be considered in parallel with scientific observations on the long-term physiological changes and post-withdrawal effects induced by finasteride and the vast array of physiological processes reliant on the appropriate function of the androgen pathway. Further study of PFS using a precision medicine approach is necessary ​(Cauci et al., 2017; Coskuner et al., 2019; La Marra, 2010; Traish, 2018)​. As patients and as patient advocates, we desperately need further molecular level investigation to be undertaken by functional geneticists, epigeneticists, scientists and epidemiologists engaged with both the emerging understanding of androgen signaling and appreciative of the full clinical and pathological picture of PFS. Although there is an increase in reported adverse events ​(Ali et al., 2015)​ associated with use of Finasteride 1mg, the numbers of PFS patients are not clearly indicative of the problem when balanced against the millions using this drug. However, considering the multisystemic nature of the persistent health changes and the current void in clinical appreciation and scientific knowledge pertaining to this condition, it is extremely likely the number of young patients experiencing insidious health problems without attribution to a causative antiandrogen to be significant. We strongly advocate for a networked approach with a focus on epigenetic assay as a necessity to move towards mechanistic understanding and ultimately disease modifying treatment. Such an approach has been urged in SBMA and significant steps towards organisation are being achieved ​(Greensmith et al., 2019; Rinaldi et al., 2015)​. The advent of adaptive genome and epigenome editing technologies make a treatment feasible following the determination of key mechanistic factors at the molecular level. The suggestion of reversibility of gene dysregulation as a consequence of AR-mediated toxicity in models of other disease states, as discussed, is suggestive of eventual therapeutic possibility.

We recommend far more thorough clinical considerations of PFS patients, particularly severe phenotypes, to be conducted in line with the clinical findings known in androgen-mediated toxicity and the previously reported findings in PFS patients. Primary research must be directed towards the underlying biological differences in the patient cohort. Patients differ greatly in symptomatically affected physiological sites and symptomatic severity, so patient selection based on symptomatic presentation is important in the design of clinical research. We strongly urge that prior 5alpha reductase inhibitor, retinoid or serotonergic drug prescription and use be ascertained in completed incidences of young male suicides in North America and European nations. Currently, completed suicides that the patient themselves or their surviving families explicitly attribute to the physical, sexual and neuropsychological damage induced by Finasteride are not appropriately attributed to the drug, as suicide is often occurring months or years after cessation when the drug is no longer in their body.

There are many avenues by which to pursue immediate clinical evaluation of PFS patients beyond appropriate basic endocrinological and urological evaluation, and these should account for the specific symptoms of individual patients. Serum creatine-kinase levels may be worthy of assessment during the post-withdrawal crash period or subsequent periods of muscle wasting, as some patients have reported elevated findings. Histological study of affected muscles, including the markedly AR-sensitive perineal muscles, would allow consideration of signs of atrophy and myogenic defects. Area calculation of the bulbocavernosus via ultrasonography has been suggested as a measure of decreased end-organ activity of androgens ​(Gupta et al., 2017)​, and this could potentially be a low-cost and non-invasive investigation in PFS patients who have experienced atrophic changes. Electromyography to assess abnormalities including signs of perineal muscle denervation may also be worthwhile. MRI protocols including localizer scans, T1-weighted imaging and 2-point Dixon sequences have proven a useful measure of muscle appearance and diffuse involvement in SBMA and could be useful in the phenotype profiling of PFS in patients with broad muscle atrophy. Dual-energy X-ray absorptiometry of bone including lumbar/thoracic spine, femur and sites of complaint, along with serum C-telopeptide testing to assess bone mineral density and trabecular bone health may be worthwhile in patients with bone-related symptomatology and who report structural alteration. Lipid profiling of patient cohorts would additionally provide insight into metabolic dysregulation.

Above all, a far greater focus on molecular level research and basic science is an overdue necessity. Due to low patient numbers, genome wide association study is unlikely to be a practical option, and full genome sequencing of existing PFS patients should be pursued to explore the potential of predisposing factors at the genomic level. Discovery of such genetic differences could eventually be used to screen for risk in young consumers considering use of antiandrogenic products or supplements. Proteomic study may yield insight into the mechanisms of toxicity. Assaying of gene expression data, study of chromatin structure and associated proteins, and methylome analysis of pathologically relevant tissues will advance understanding of deregulated genes as driving factors in this new and novel disease that develops following endocrine disruption. PFS patients are usually in good health prior to use of the associated antiandrogenic substance and can extraordinarily rapidly develop secondary disease states, many of which are associated with advanced age. Advancing the understanding of PFS is therefore likely to yield important mechanistic insights into a diverse array of pathologies. Comparative epigenetic profiling of patients suffering from the disease states following Accutane and SSRI antidepressant use could provide grounds for the wider consideration of the hypothesis regarding a common post-androgen deprivation syndrome and thus a ground-breaking discovery.

Page Bibliography

  1. Ali, A. K., Heran, B. S., & Etminan, M. (2015). Persistent Sexual Dysfunction and Suicidal Ideation in Young Men Treated with Low-Dose Finasteride: A Pharmacovigilance Study. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 687–695. https://doi.org/10.1002/phar.1612
  2. Cauci, S., Chiriacò, G., Cecchin, E., Toffoli, G., Xodo, S., Stinco, G., & Trombetta, C. (2017). Androgen Receptor ( AR ) Gene (CAG)n and (GGN)n Length Polymorphisms and Symptoms in Young Males With Long-Lasting Adverse Effects After Finasteride Use Against Androgenic Alopecia. Sexual Medicine, e61–e71. https://doi.org/10.1016/j.esxm.2016.11.001
  3. Coskuner, E. R., Ozkan, B., & Culha, M. G. (2019). Sexual Problems of Men With Androgenic Alopecia Treated With 5-Alpha Reductase Inhibitors. Sexual Medicine Reviews, 277–282. https://doi.org/10.1016/j.sxmr.2018.07.003
  4. Gashaw, I., Ellinghaus, P., Sommer, A., & Asadullah, K. (2011). What makes a good drug target? Drug Discovery Today, 1037–1043. https://doi.org/10.1016/j.drudis.2011.09.007
  5. Greensmith, L., Pradat, P. F., Sorarù, G., & Pennuto, M. (2019). 241st ENMC international workshop: Towards a European unifying lab for Kennedy’s disease. 15–17th February, 2019 Hoofddorp, The Netherlands. Neuromuscular Disorders, 716–724. https://doi.org/10.1016/j.nmd.2019.07.008
  6. Gupta, N., Carvajal, M., Jurewicz, M., & Gilbert, B. R. (2017). Bulbocavernosus muscle area as a novel marker for hypogonadism. Asian Journal of Urology, 3–9. https://doi.org/10.1016/j.ajur.2016.11.002
  7. La Marra, F. (2010). The post-finasteride syndrome in patients with alopecia. university of Udine.
  8. Rinaldi, C., Malik, B., & Greensmith, L. (2015). Targeted Molecular Therapies for SBMA. Journal of Molecular Neuroscience, 335–342. https://doi.org/10.1007/s12031-015-0676-5
  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. https://doi.org/10.1007/s11930-018-0161-6