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Gene Expression Study of Post-Finasteride Syndrome patients at Baylor College of Medicine Published
Landmark study demonstrated evidence of significant Androgen Receptor overexpression and symptom-relevant pathway deregulation in PFS patients
In a key investigation undertaken at Baylor College of Medicine under Dr Mohit Khera, Howell et al. reported gene expression analysis of penile skin samples taken from 26 Post-Finasteride Syndrome patients (median age 38 years) and compared with analysis of samples from 26 control subjects.
RNA microarray analysis revealed that 1,446 genes were found to be significantly over-expressed and 2,318 genes significantly underexpressed in studied PFS patients. The presented evidence of these gene expressions correlated to observed biological differences and symptoms reported by patients in the investigation, providing strong evidence of a biological aetiology underlying the devastating multisystem symptoms of Post-Finasteride Syndrome.
As a noted key finding, androgen receptor expression (AR) was found to be significantly higher in patients compared to controls. The AR is expressed across multiple bodily tissues and systems including the reproductive, genitourinary, nervous, musculoskeletal, cardiovascular, and immune systems. Recent research and understanding has shown the AR to be a critical pleiotropic regulator of gene expression in tissues beyond its key role in the male reproductive system, and that too much androgen signaling is significantly detrimental, as well as too little. Upregulation of the AR is a known mechanistic response under conditions of androgen deprivation, such as castration resistant prostate cancer.
The authors suggest that AR overexpression, in response to an androgen-deficient state, may negatively affect multiple tissues throughout the body and could be responsible for the sexual symptoms of Post-Finasteride Syndrome. These include atrophic penile structural changes, which they previously reported case-controlled ultrasound results regarding, and many others such as orgasm dysfunction, genital pain, watery semen. They suggest if overexpressed in other tissues, the androgen receptor may be involved in other symptomatic domains, including cognitive symptoms.
Widespread pathway deregulation was observed relevant to the aforementioned reproductive, genitourinary, nervous, musculoskeletal, cardiovascular, and immune systems, much of which is mentioned in our summary of the report. Crucially, these findings were relevant to symptoms patients in the study had reported as a result of 5alpha reductase inhibitor exposure.
The relevant finding of downregulation of the 17-beta hydroxysteroid dehydrogenase enzymes provide a potential explanation for neurosteroid deregulation in absence of active 5alpha reductase inhibition. Downregulation of a key cortisol-inhibiting gene and upregulation of inflammatory genes provides a basis for a state of chronic physiological stress in PFS.
Despite this data being unable to demonstrate causality, the evidence of significant deregulation of critical biological pathways in these PFS patients is in the context of correlated biological observations and symptoms reported as induced by the drug. This data should therefore provide informative direction for future research. Research should now move on from hypotheses-focused investigations that cannot account for key features and the broad multisystem symptoms of the syndrome, and focus on the identification of potential predisposing factors, potentially genetic, and plausible mechanistic pathological drivers of this broad and apparently tissue-specific deregulation, including consideration of AR-related epigenetic mechanisms. The study also justifies focus on the use of symptom and AR-relevant patient tissue in epigenetic investigations, as overexpression was not reported in the investigation by Basaria et al. who conducted a limited assay using back skin samples. However, it confirms the finding of AR overexpression in penile skin by Di Loreto et al.
Science as a Candle in the Dark
This is a timely report and should be considered alongside recent animal studies, including one concluding that the drug induces AR-relevant transgenerational changes and probably has epigenetic side effects, as well as the detection of significant adverse event reporting signals in young men exposed to the drug for hair loss.
This data should be seen as a watershed moment. Post-Finasteride patients and their families still too often suffer what amounts to gaslighting when seeking medical support for an adverse drug reaction. We hope this provides hope that the tide of dismissal and disregard will be turned by scientific understanding. We are currently networking with scientists to arrange further research building in this direction. Please subscribe to our social channels and this mailing list to stay up to date with these coming opportunities.
The significant epigenetic deregulation reported by the Baylor team provides a strong case for the biologic aetiology of Post-Finasteride Syndrome as an epigenetic deregulation resulting from androgen deprivation in young predisposed consumers. The predisposition is unknown and there is no way currently to predict who will be affected. A participant of the study, a professor of criminology, who took his life due to catastrophic physical, sexual and cognitive symptoms had taken only 9 pills of finasteride before persistently worsening upon withdrawal - a key clinical feature of Post-Finasteride Syndrome. His mother has told his tragic story for our YouTube channel, and this will be shared in the coming months. If you are a patient or loved one who is suffering with PFS, please consider volunteering for a video interview about your experience for or YouTube series. These valuable personal accounts both inform and highlight the human cost of this stigmatising and life altering condition. You can get in touch via our contact page.
Reported Harms Must Be Documented, and Consumers Warned
Responsible clinicians must ensure young patients reporting significant and lasting harm after taking 5alpha reductase inhibitors have their cases well documented and appropriately reported to regulatory agencies.
Clinicians counselling patients for hair loss have a responsibility to warn patients that some consumers may, without predictive factors, experience serious and permanent physical, sexual and cognitive symptoms that are not yet understood or treatable.
We thank the team at Baylor College of Medicine and the Post-Finasteride Syndrome Foundation for organising this important investigation.