Deregulated Androgen Receptor in PFS
In our recent online publication:
we suggested that site-specific epigenetic changes induced by androgen deprivation as a result of 5AR inhibition may result in a pathological AR upregulation, which in turn could be a key driver of the broad hypogonadic symptomatology typically experienced by Post-Finasteride Syndrome (PFS) patients.
Di Loreto et al. were the first to report significant upregulation at the Androgen Receptor level (Di Loreto et al., 2014) and it has subsequently been suggested that local AR deregulation could play a pathological role in PFS (Than et al., 2018; Traish, 2018).
We believe that these findings could potentially explain the apparent lack of androgenic action despite often normal androgen levels in patients.
As discussed, as the CAG trinucleotide sequence extends in the N-terminal domain of the AR, there is a consequent functional decline in transcriptional efficiency which is seemingly associated with a compensatory increase in androgen levels. However, at longer repeat lengths, high androgen levels can exert a deleterious and ultimately toxic response. Crucially, polyglutamine expansion is not the only way ligand-dependent toxicity can be conferred to the AR protein, and overexpression of the wild type AR can cause a paradoxical loss of function and toxic gain of function. This is reflective of evidence in other polyglutamine diseases that point to gain of native protein function underlying pathology (Paulson et al., 2017). It is now appreciated that balanced gene expression is vital for homeostasis, and overexpression of wild-type proteins causes disease states in humans (Ohshima et al., 2017; Shastry, 1995). Multiple studies demonstrate that, while seemingly paradoxical, sufficient increases in AR expression converge with loss of function phenotypes, with an inverse U‐shaped curve representative of AR gene dose response in tissues. The pathological consequence of overexpression of the AR is therefore coherent with Prelich’s observation that overexpression of proteins mimics a loss of function and interferes with its function antimorphically.
Our own patient research data shows that roughly 20% of all surveyed patients experienced a change to their “Frequency of infectious or viral illnesses (including common colds, flu etc)”. Of those, around 60% of respondents reported a decrease in frequency of “infectious or viral illnesses”. In other words, PFS patients are reporting that they tend to get sick less often and are less affected by common colds or the flu, compared to before acquiring PFS:
COVID19 Driven by Androgen Receptor
Very recently, Wambier et al. came to following conclusion regarding COVID-19:
The androgen-driven COVID19 pandemic theory, based on the androgen receptor activation for the transcription of transmembrane protease, serine 2 (TMPRSS2), explores possible implications in risk stratification and transmissibility. Androgen receptor activity is required for the transcription of TMPRSS2 gene. TMPRSS2 activity is regarded as essential for viral entry and replication in infected hosts (Hoffmann et al., 2020).
Several studies have demonstrated that androgen sensitivity is associated with the CAG repeat in the first exon of the androgen receptor gene (AR). Shorter CAG repeat length pre-dispose men to develop androgenetic alopecia, acne and oily skin; therefore, we believe that CAG repeat in the AR gene may be associated with increased COVID-19 disease severity and mortality.
Following the androgen-driven COVID-19 theory, subjects with increased androgen receptor activity, either through androgen receptor gene polymorphism or through hyperactivation by androgen hormones are predisposed to increased viral load, which would reflect on pronounced symptoms and transmissibility from cell lining of the airways and digestive tract (Wambier et al., 2020).
Fig. 2 (Wambier et al., 2020)
Our hypothesis, based on the Di Loreto study and our own literature review, states that site specific overexpression of the Androgen Receptor in PFS patients results in a deleterious gain of function and consequent loss of typical function, entailing an androgen resistant phenotype. Wambier et al. propose that AR signaling is the key driver for COVID19 transmissibility and outcome. If both are correct, and with consideration to our survey data, PFS patients may differ from the typical COVID19 outcome patterns seen in the general population.
Please note that a subset of patients report a higher frequency of infectious or viral illnesses. If you are a PFS patient, do not assume that you are immune to the Corona Virus based on this hypothesis. Stay safe and adhere to health authority guidelines.
- Di Loreto, C., La Marra, F., Mazzon, G., Belgrano, E., Trombetta, C., & Cauci, S. (2014). 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, e100237. https://doi.org/10.1371/journal.pone.0100237
- Than, J. K., Rodriguez, K., & Khera, M. (2018). Post-finasteride Syndrome: A Review of Current Literature. Current Sexual Health Reports, 152–157. https://doi.org/10.1007/s11930-018-0163-4
- 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
- Wambier, C. G., Goren, A., Ossimetha, A., Nau, G., & Qureshi, A. A. (2020). Androgen-driven COVID-19 pandemic theory. Unpublished. https://doi.org/10.13140/RG.2.2.21254.11848