Post-Finasteride Syndrome Patients: Is There Differential Gene Expression?

21 December 2023 – Finasteride is a medication used for the treatment of benign prostatic hyperplasia (on the market as Proscar (5mg) since 1992 for this indication) and male pattern hair loss (on the market as Propecia (1mg) since 1997 for this indication). Finasteride is a type II and type III 5α-reductase inhibitor, 5α-reductase being an enzyme that converts testosterone dihydrotestosterone (DHT).

For quite some time now, there has been the discussion whether Finasteride (Propecia) causes long-term sexual dysfunction in some men after stopping drug treatment. There are case reports of persistent diminished libido or erectile dysfunction after stopping the drug and the FDA has updated the Finasteride (Propecia) label to inform people of these reports. A 2010 review found moderate quality evidence that Finasteride(Propecia) increased the risk of sexual dysfunction, but not that people stopped using it because of sexual side effects.

Since we at thasso are in the -Omics of serious Adverse Drug Reactions, we asked for a long time if there are genetic defects out there in the male population that cause male pattern hair loss the first place and then lead to the Finasteride Syndrome in some male individuals and and not in the majority of others who have taken finasteride too.

Research into the genetic background of male pattern hair loss recently has shown that among more than about hundred candidate genes, there are a number of autosomal genes such as RSPO2, PGDFA, PRR23B, and WNT10A could play a role in male pattern hair loss. In addition, X chromosome based genes included the androgen receptor (AR), which has been well established as a baldness associated gene [32], along with its upstream (EDA2R) and downstream (OPHN1) genes. EDA2R plays a role in the maintenance of hair and teeth as part of the tumor necrosis factor receptor. Onset of male pattern baldness could be influenced by EDA2R via activation of the nuclear proto-oncoprotein c-Jun, which is linked to transcription activation of AR. Two other genes included in the gene-based findings, OPHN1 (and ZC4H2) have previously been associated with X-linked mental retardation.

In contrast, the genes (or variants thereof) rendering individuals predisposed to PFS are not yet known. However, in a recent study, noticeable differences in the expression of genes have been detected between sufferers of PFS and non-sufferers. The study aimed at determination whether differences in gene expression, especially in relevant biologic pathways, exist between patients post-finasteride syndrome symptoms and healthy controls. Issues such as an organic etiology underpinning post-finasteride syndrome, a constellation of persistent sexual, neuropsychiatric, and somatic symptoms reported by men exposed to 5-alpha-reductase inhibitors (5ARIs), as well as persistent changes in neurosteroid levels or androgen receptor expression should become more understandable based on the profile of gene expression.

In fact, in this single center prospective case-control study men 18 years and older being evaluated for sexual dysfunction (study) or circumcision (control) were eligible for inclusion. Twenty-six men with a history of 5ARI use reporting symptoms consistent with post-finasteride syndrome were included in the patient group. Twenty-six men consented to inclusion in the control group.

Gene expression of cells from penile skin samples from twenty-six men of median age 38 years in the study group was compared with
that from twenty-six men of median age 41 years in the control group, with 1,446 genes significantly over-expressed and 2,318 genes significantly under-expressed in study patients. Androgen receptor expression was significantly higher in study patients compared to controls. Serum levels of androgen receptor activity markers 5α-androstanediol  or 3α-androstanedione revealed no significant differences. No significant differences were found between the number of trinucleotide repeats.The clinical  implications of the study was the found evidence of gene expression correlating with observed biologic differences in patients with Post- Finasteride Syndrome. This study is the first to consider and demonstrate gene expression differences in patients with PFS as a potential etiology of sexual dysfunction.

What remains to understand is which genes (or variants thereof) are differently regulated in their expression in PFS-individuals versus control individuals not suffering from PFS. Based on the information obtained in this study, it should now be possible to identify the genes differently expressed and see which of these genes variants predispose (young) men to PFS.Once these genes have bee identified, prospective genotyping of men would become an option in order to avoid exposer individuals at risk to develop PFS from taking Finasteride in the first place.

Note here that thasso has discussed some of the serious consequences for young men suffering from PFS a while ago. There are also groups on Facebook which maintain intensive exchanges among affected people. See also this discussion on PFS and its complexicity in the real world: