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Differential Gene Expression in Post-Finasteride Syndrome Patients
Skyler Howell1, Weitao Song2, Alexander Pastuszak3
1Division of Urology, Department of Surgery, University of Texas McGovern Medical School at Houston, Houston, TX, USA.
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. Howell S, Song W, Pastuszak A, et al. Differential Gene Expression in Post-Finasteride Syndrome Patients. J Sex Med 2021;18:1479-1490.
Insights
This study found significant gene expression differences in penile tissue from men with post-finasteride syndrome, suggesting a biological basis for persistent symptoms after using 5-alpha-reductase inhibitors (5ARIs). These findings highlight potential molecular changes contributing to the condition.
Area of Science:
- Molecular Biology
- Genetics
- Endocrinology
Background:
- Post-finasteride syndrome (PFS) involves persistent sexual, neuropsychiatric, and somatic symptoms after 5-alpha-reductase inhibitor (5ARI) use.
- The underlying organic etiology of PFS, particularly neurosteroid changes or androgen receptor alterations, remains debated.
Purpose of the Study:
- To investigate differential gene expression in penile tissue between men with PFS and healthy controls.
- To identify specific biological pathways and genes associated with PFS symptoms.
Main Methods:
- A prospective case-control study involving 26 men with PFS and 26 healthy controls.
- Analysis of gene expression in penile skin cells using samples collected between March 2013 and September 2018.
- Comparison of gene expression profiles, focusing on genes related to neurosteroid levels and androgen receptor activity.
Main Results:
- Significant differences in gene expression were observed, with 1,446 genes over-expressed and 2,318 under-expressed in PFS patients.
- Androgen receptor expression was significantly higher in the PFS group compared to controls.
- No significant differences were found in serum markers of androgen receptor activity or trinucleotide repeats.
Conclusions:
- This study provides evidence of distinct gene expression patterns in patients with PFS, suggesting a biological basis for the syndrome.
- The findings indicate that alterations in gene expression may contribute to the persistent symptoms experienced by some men after 5ARI use.
- Healthcare providers prescribing 5ARIs should be aware of these potential biological differences and counsel patients accordingly.
