Differential Gene Expression in Post-Finasteride Syndrome Patients
Howell et al., 2021
“exposure to 5ARI could lead to permanent changes in genetic expression through unknown mechanisms which cause the changes we were able to measure and analyze.”
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.
Conducting RNA microarray analysis, 1,446 genes were found to be significantly over-expressed and 2,318 genes significantly underexpressed in studied Post-Finasteride Syndrome patients. The presented evidence of these differing gene expressions correlated to observed biological differences in PFS patients and the symptoms they were reporting.
Of particular interest, androgen receptor expression (AR) was found to be significantly higher in patients compared to controls, in the absence of differences in serum markers indicating AR activity or trinucleotide repeat variation. The authors suggested that AR overexpression in response to an androgen-deficient state may negatively affect multiple tissues throughout the body, could be responsible for the sexual symptoms of Post-Finasteride Syndrome, and - if overexpressed in other tissues - may be involved in other symptomatic domains, including cognitive symptoms.
As AR is a significant regulator and coregulated by many other genes, genes of interest that were differentially expressed were identified by microarray analysis that function as coregulators of the AR. This included 17-beta-hydroxysteroid dehydrogenase enzymes, suggesting a potential mechanism for disrupted neurosteroid synthesis independent of active 5-alpha reductase inhibition.
Pathway analysis indicated alterations in gene expressions relevant to biological processes affecting the sexual, genitourinary, neurological, musculoskeletal, cardiovascular, metabolic, and immune systems. With relevance to penile tissue changes, pathways involving extracellular matrix regulation, cell junction organization, and connective tissue health were down-regulated.
Patients in the study reported musculoskeletal complaints including fatigue, muscle atrophy, and joint pain, as well as skin changes and visual disturbances. With relevance to these, pathway analysis revealed upregulation in pathways affecting skin development, epidermis development, and “establishment of the skin barrier”. Ossification was also upregulated. Down-regulated clusters included skeletal system development, muscle structure development, sensory organ development, sensory organ (visual) development, and connective tissue development. Genes involved in cardioprotection; bone mineralization; normal brain development, function and apoptosis regulation were also underexpressed.
Findings such as downregulation of a negative regulator of cortisol, implying increased cortisol secretion, as well as overexpression of inflammatory genes, support the existence of a chronic stress state in Post-Finasteride Syndrome relevant to symptoms reported such as palpatations, cold flashes and rapid ageing, and compounding other problems.
Data showed that many genes affecting gene expression were altered, and the authors hypothesised that exposure to 5-alpha reductase inhibitors could lead to permanent changes in genetic expression through unknown mechanisms, causing the measured and analysed changes.
This study represents the first significant gene expression analysis of Post-Finasteride Syndrome patients, and has correlated a wide range of PFS symptoms to deregulated gene expressions through pathway analysis. The authors concluded that more research on downstream processes of protein expression, mechanisms regulating gene expression in Post-Finasteride Syndrome, and identification of risk factors, particularly genetic. They also state that at this time patients should be counselled on the possibility of permanent side effects after use of 5-alpha reductase inhibitors.
