Differential Gene Expression in Post-Finasteride Syndrome Patients

Abstract

Background 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), is debated. Persistent changes in neurosteroid levels or androgen receptor expression have been implicated. Aim To determine whether differences in gene expression, especially in relevant biologic pathways, exist between patients reporting post-finasteride syndrome symptoms and healthy controls. Methods This was a single center, prospective case-control study taking place between March 2013 and September 2018. 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. Outcomes The primary outcome measure is gene expression data for genes affecting neurosteroid levels and androgen receptor activity from penile skin cells. RESULTS Gene expression of cells from penile skin samples from twenty-six men of median age 38 years (IQR, 33-42) in the study group was compared with that from twenty-six men of median age 41 years (IQR, 35-62) in the control group (P = .13), 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 (9.961 vs 9.494, adjusted P value = .01). Serum levels of androgen receptor activity markers 5α-androstanediol (0.950 ng/mL [0.749-1.587] vs 0.949 [0.817-1.337], P = .34) or 3α-androstanedione (3.1 ng/mL [1.925-5.475] vs 6.7 [3.375-11.4], P = .31) revealed no significant differences. No significant differences were found between the number of trinucleotide repeats (21.5 [20-23.75], 22 [19-25], P = .94). Clinical Implications In this study we present evidence of gene expression correlating with observed biologic differences in patients with post-finasteride syndrome; providers who prescribe 5ARIs should be aware and advise their patients accordingly. Strengths & Limitations Strengths of this study include the evaluation of multiple proposed etiologies for post-finasteride syndrome. The study is also strengthened by the fact that not all data matched the initial hypotheses, qualifying the argument for the existence of PFS. Limitations include potential selection bias arising from more severe phenotypes seeking care; lack of gene expression data prior to 5ARI exposure; lack of non-penile tissue samples supposedly involved; and a lack of mechanistic data to imply causality. CONCLUSION This study is the first to consider and demonstrate gene expression differences in patients with PFS as a potential etiology of sexual dysfunction.

The Interplay between Finasteride-Induced Androgen Imbalance, Endoplasmic Reticulum Stress, Oxidative Stress, and Liver Disorders in Paternal and Filial Generation

“…Research conducted on a cell line derived from Caucasian human prostate carcinoma (LNCap), in a model of androgen-dependent prostate cancer, revealed that the exposure of cells to Fin for 1–6 months increased AR expression [ 41 ]. A study reporting symptoms consistent with post-finasteride syndrome (PFS) was conducted on samples of penile skin from 26 men with a history of using 5-alpha-reductase inhibitors, and showed significantly higher AR expression compared to the controls [ 42 ]. It has also been demonstrated that AR and the gene expression of UPR are correlated in prostate cancer.…”

From organ injury to disability: a proposed model for 5-alpha reductase inhibitor syndrome

“…27 higher expression of AR in penile tissue of post-finasteride patients. 94 Androgen mediation of post-ischemic neoangiogenesis Androgens, AR and age also mediate the response to ischemic events. Lam et al…”

“…Human and animal studies have identified differences in neuroactive steroid levels, gut microbiota composition and gene expression persisting after discontinuation of finasteride. 33,80,94,116,117 The neuroendocrine system, microbiome and epigenome are intricate, sensitive domains which may reflect diet, environment, health conditions, medication exposures, sleep and stress. Therefore, even a robust finding of post-5ARI differences in these domains does not necessarily explain the pathogenesis of PD-5ARI.…”

“…A recent study found widespread epigenetic changes in penile tissue biopsies of post-5ARI patients with long-term symptoms. 94 Here too, hypoxic memory and epigenetic consequences of ischemia could explain the emergence of such changes.…”

Exploring rat corpus cavernosum alterations induced by finasteride treatment and withdrawal

“…18,19 Interestingly, these side effects may persist after the drug suspension, inducing the so-called post-finasteride syndrome (PFS). 9,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] The effects of finasteride treatment were also reported in animal models. For instance, finasteride treatment in castrated rats decreased erectile response, although receiving T replacement 35,36 and in control male rats, it decreased intracavernosal pressure during electrical stimulation of cavernous nerves.…”