Research on 5-alpha reductase enzyme & expression

5-alpha reductase enzyme & expression

IN BRIEF: 5-alpha reductase has three isozymes: types 1, 2 and 3. Finasteride and dutasteride both inhibit 5-alpha reductase types 2 and 3, while dutasteride also strongly inhibits 5-AR type 1 (more on pharmacology here). SRD5A2, the gene encoding 5-AR type 2, is expressed in the male reproductive system, liver and lung (see chart) as well as the brain per Castelli et al.

Systems affected in the post-5-ARI disorder have a notable overlap with the distribution of SRD5A2 (such as the reproductive system and hypothalamus). This suggests a hypothesis that the post-5-ARI disorder could result from disruption in pathways involving 5-AR type 2.

Ge et al identified a pathway of possible relevance: inflammation in the prostate led to methylation of SRD5A2, which silenced expression of the enzyme. Separately, Melcangi et al reported methylation of SRD5A2 in cerebrospinal fluid of men with post-finasteride syndrome. There is a possibility that the post-5-ARI disorder may involve methylation of SRD5A2.

In other background, research on 5-alpha reductase deficiency, a disorder of sexual development, provided the rationale for the development of finasteride.

Expression of SRD5A2 gene by tissue type. There was significant expression of SRD5A2 in liver, prostate, bladder, testis and lung. Source: NCBI Gene

Background

Azzouni F, Godoy A, Li Y, Mohler J. The 5 alpha-reductase isozyme family: a review of basic biology and their role in human diseases. Adv Urol. 2012. doi:10.1155/2012/530121 • PubMed • PMC full text

Castelli MP, Casti A, Casu A, et al. Regional distribution of 5α-reductase type 2 in the adult rat brain: an immunohistochemical analysis. Psychoneuroendocrinology. 2013. doi:10.1016/j.psyneuen.2012.06.008 • PubMed • PMC full text

NCBI Gene. 5-alpha reductase types 1–3. SRD5A1 • SRD5A2 • SRD5A3

Yamana K, Labrie F, Luu-The V. Human type 3 5α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride. Horm Mol Biol Clin Investig. 2010 Aug 1. doi:10.1515/HMBCI.2010.035 • PubMed

2020s

Jin R, Forbes C, Miller NL, et al. Glucocorticoids are induced while dihydrotestosterone levels are suppressed in 5-alpha reductase inhibitor treated human benign prostate hyperplasia patients. Prostate. 2022. doi:10.1002/pros.24410 • PubMed

Lin ZM, Fan DD, Jin S, Liu ZL, Niu YN. Methylated CpG dinucleotides in the 5-α reductase 2 gene may explain finasteride resistance in benign prostatic enlargement patients. Asian J Androl. 2021. doi:10.4103/aja.aja_63_20 • PubMed • PMC full text

Liu Z, Lin Z, Cao F, et al. Upregulation of mir-1199-5p is associated with reduced type 2 5-α reductase expression in benign prostatic hyperplasia. BMC Urol. 2022. doi:10.1186/s12894-022-01121-5 • PubMed • PMC full text

Wang Z, Deng T, Long X, et al. Methylation of SRD5A2 promoter predicts a better outcome for castration-resistant prostate cancer patients undergoing androgen deprivation therapy. PLoS One. 2020. doi:10.1371/journal.pone.0229754 • PubMed• PMC full text

Xiao Q, Wang L, Supekar S, et al. Structure of human steroid 5α-reductase 2 with anti-androgen drug finasteride. Res Sq [Preprint]. 2020. doi:10.21203/rs.3.rs-40159/v1 • PubMed • PMC full text

Xue B, Wu S, Sharkey C, et al. Obesity-associated inflammation induces androgenic to estrogenic switch in the prostate gland. Prostate Cancer Prostatic Dis. 2020 Sep. doi:10.1038/s41391-020-0208-4 • PubMed • PMC full text

2010s

Basaria S, Jasuja R, Huang G, et al. Characteristics of men who report persistent sexual symptoms after finasteride use for hair loss. J Clin Endocrinol Metab. 2016. doi:10.1210/jc.2016-2726 • PubMed • PMC full text

Bissegger S, Langlois VS. Androgens modulate gene expression and specific DNA methylation pattern of steroid 5α-reductases in the frog Silurana tropicalis. Gen Comp Endocrinol. 2016. doi:10.1016/j.ygcen.2016.03.021 • PubMed [Study does not involve finasteride]

Ge R, Wang Z, Bechis SK, et al. DNA methyl transferase 1 reduces expression of SRD5A2 in the aging adult prostate. Am J Pathol. 2015. doi:10.1016/j.ajpath.2014.11.020 • PubMed • PMC full text

[Commentary] Isaacs JT. Lessons learned about prostatic transformation from the age-related methylation of 5α-reductase type 2 gene. Am J Pathol. 2015 Mar. doi:10.1016/j.ajpath.2015.01.001 • PubMed • PMC full text

Melcangi RC, Casarini L, Marino M, et al. Altered methylation pattern of the SRD5A2 gene in the cerebrospinal fluid of post-finasteride patients: a pilot study. Endocrine Connections. 2019. doi:10.1530/EC-19-0199 • PubMed • PMC full text

Rongbin G, Wang Z, Bechis S, et al. Abstract 1052: Variable expression of 5-alpha reductase 2 in the aging adult prostate is regulated by DNA methylation. Cancer Research. 2015;75(15_Supplement):1052. doi:10.1158/1538-7445.AM2015-1052

Upreti R, Hughes KA, Livingstone DE, et al. 5α-reductase type 1 modulates insulin sensitivity in men. J Clin Endocrinol Metab. 2014. doi:10.1210/jc.2014-1395 • PubMed • PMC full text

Wang Z, Hu L, Salari K, et al. Androgenic to oestrogenic switch in the human adult prostate gland is regulated by epigenetic silencing of steroid 5α-reductase 2. J Pathol. 2017. doi:10.1002/path.4985 • PubMed • PMC full text

Windahl SH, Andersson N, Börjesson AE, et al. Reduced bone mass and muscle strength in male 5α-reductase type 1 inactivated mice. PLoS One. 2011. doi:10.1371/journal.pone.0021402 • PubMed • PMC full text

2000s

Oakes CC, La Salle S, Smiraglia DJ, Robaire B, Trasler JM. A unique configuration of genome-wide DNA methylation patterns in the testis. Proc Natl Acad Sci U S A. 2007. doi:10.1073/pnas.0607521104 • PubMed • PMC full text

1990s

Berman DM, Tian H, Russell DW. Expression and regulation of steroid 5 alpha-reductase in the urogenital tract of the fetal rat. Mol Endocrinol. 1995. doi:10.1210/mend.9.11.8584033 • PubMed

“In the adult prostate, 5 alpha-reductase gene expression is under feedforward control, in which the product of the enzyme, dihydrotestosterone, stimulates the expression of the gene.”

Normington K, Russell DW. Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions. J Biol Chem. 1992. Open access • PubMed

Reyes EM, Camacho-Arroyo I, Nava G, Cerbón MA. Differential methylation in steroid 5 alpha-reductase isozyme genes in epididymis, testis, and liver of the adult rat. J Androl. 1997. doi:10.1002/j.1939-4640.1997.tb01941.x • PubMed • Via journal site

[⚠️ Supported by a grant from Glaxo] Thigpen AE, Silver RI, Guileyardo JM, Casey ML, McConnell JD, Russell DW. Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression. J Clin Invest. 1993 Aug;92(2):903-10. doi:10.1172/JCI116665 | PubMed | PMC full text

Viger RS, Robaire B. The mRNAs for the steroid 5 alpha-reductase isozymes, types 1 and 2, are differentially regulated in the rat epididymis. J Androl. 1996. doi:10.1002/j.1939-4640.1996.tb00583.x • PubMed • Via journal site