SRD5A2 and emerging therapies in androgen-driven disorders

Abstract

Benign prostatic hyperplasia (BPH) is one of the most prevalent urological disorders in aging men. Althoughmedical therapies are widely used, truly effective long-term treatments remain limited. Among the most commonly prescribed drugs are 5-alpha reductase inhibitors (5ARIs), which alleviate symptoms and slow disease progression by inhibiting steroid 5-alpha reductase (SRD5A) enzymes, particularly the SRD5A1 and SRD5A2 isoforms. SRD5A2, the dominant isoform in the prostate, plays a pivotal role in androgen metabolism by converting testosterone to dihydrotestosterone (DHT), a potent driver of prostate growth. Proper regulation of SRD5A2 is essential for maintaining the balance between androgenic and estrogenic signaling, thereby supporting normal prostate physiology. Emerging evidence links SRD5A2 alterations, such as genetic polymorphisms, epigenetic silencing, and inflammation-induced changes to disease risk and progression, positioning these factors as promising biomarkers for personalized therapy.. Beyond BPH, SRD5A2 has also been implicated asa potential therapeutic target in prostate cancer and androgenic alopecia. This translational reviewsynthesizes recent advances in SRD5A2 biology, emphasizing its clinical relevance in BPH, prostate cancer, and other androgen-mediated conditions. We also discuss current limitations of SRD5A2-targeted therapies and propose future strategies to enhance the efficacy of 5ARI-based treatments.

Introduction

The prostate is the only glandular organ in the human body that continues to grow throughout life¹. Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate, characterized by stromal and epithelial proliferation within the transition zone². It is the most common prostate disorder in men over 50, with prevalence increasing alongside life expectancy^3,4, affecting approximately 5–6% of men aged 40–64 and 29–33% of those 65 and older⁵. BPH is a major cause of lower urinary tract symptoms (LUTS) and can lead to bladder outlet obstruction, urinary tract infections, and acute urinary retention^6,7. Current first-line treatments include α1-adrenergic receptor antagonists (α-blockers), alone or in combination with 5α-reductase inhibitors (5ARIs). 5ARIs act by inhibiting steroid 5α-reductase (SRD5A), thereby lowering intraprostatic dihydrotestosterone (DHT) levels and reducing prostate volume. While effective for some,, 5ARIs slow LUTS progression by only about 34%, leaving a substantial proportion of patients unresponsive and ultimately requiring surgical intervention^8–10. The biological basis for this variability remains poorly understood, representing a major gap in effective BPH management. In this review, we adopt a translational research perspective, integrating recent mechanistic insights into SRD5A2 biology with their potential clinical implications. While SRD5A2 is also implicated in prostate cancer and other androgen-related disorders, BPH remains our primary clinical focus. We discuss how genetic, epigenetic, and inflammation-associated regulation of SRD5A2 may influence treatment response, evaluate the limitations of current SRD5A2-targeted therapies, and outline future strategies for more personalized and effective interventions. By explicitly bridging basic mechanisms with clinical applications, we aim to clarify how SRD5A2 biology informs patient care and where new opportunities for therapeutic development may lie.

Importance of SRD5A2 in prostate

Prostate homeostasis and growth are critically dependent on androgen signaling. Testosterone, the primary androgen, is secreted by the testes and subsequently reaches prostatic tissue, where it is converted to DHT by three steroid 5α-reductase isozymes: SRD5A1, SRD5A2, and SRD5A3. Among these, SRD5A2 is the dominant isozyme in the prostate. DHT binds to the androgen receptor (AR) with two- to five-fold higher affinity than testosterone and amplifies AR signaling up to ten-fold^11,12. The activated androgen–AR complex translocates to the nucleus of both epithelial and stromal cells, promoting the expression of growth factors such as keratinocyte growth factor, epidermal growth factor and insulin-like growth factors (IGFs). These growth factors play a key role in maintaining the delicate balance between cell proliferation and apoptosis, which is essential for normal prostate development and homeostasis¹¹.

SRD5A2 in Prostate Development

Prostate is derived from the urogenital sinus, DHT is essential for the development of the prostate and virilization during fetal growth, and mediates sexual maturation during puberty¹³. SRD5A2 is constitutively expressed in male accessory reproductive tissues and genital skin throughout lifespan¹⁴. During puberty, rising testosterone levels stimulate further prostate growth, with SRD5A2 ensuring adequate DHT production to support the final stages of glandular maturation¹⁵. This process includes epithelial branching morphogenesis, stromal differentiation, and the establishment of the prostate's functional zones (peripheral, central, and transition zones)^16,17. Disruptions in SRD5A2 expression due to genetic mutation or polymorphism at birth is associated with an autosomal recessive disorder named SRD5A2 deficiency, which is associated with incomplete prostate formation and ambiguous genitalia, underscoring the enzyme’s fundamental developmental role^18,19. In adult men, SRD5A2 continues to maintain tissue homeostasis by balancing cell proliferation, apoptosis, and secretory functions within the prostate². Through its role in modulating DHT levels, SRD5A2 ensures that androgen-dependent signaling pathways remain properly controlled, thus preserving normal tissue architecture and preventing excessive cellular growth.

SRD5A2 in BPH

SRD5A2 is critical in the pathogenesis of BPH. The enzyme is predominately expressed in stromal and part of epithelial compartments that undergo hyperplastic changes^12,20. By locally generating high levels of DHT, this enzyme influences cell proliferation, tissue remodeling, and the overall androgenic environment that drives prostatic enlargement²¹. DHT binds to AR with a higher affinity than testosterone, ensuring a more robust and prolonged activation of androgenic signaling pathways²². Once bound, the DHT–AR complex translocates to the nucleus, where it modulates the expression of multiple genes involved in cell cycle progression, proliferation, and survival²³. This robust androgenic drive not only stimulates the replication of prostate cells but also alters the local tissue microenvironment by influencing the production of growth factors and cytokines. For example, fibroblast growth factors (FGFs) and IGFs can be upregulated, further fueling the hyperplastic process by enhancing both stromal and epithelial proliferation²⁴. Additionally, DHT signaling may increase the expression of certain extracellular matrix components, contributing to a structural framework that favors continued nodular expansion²⁵. Prolonged or excessive SRD5A2 activity amplifies these processes, intensifying the hormonal and growth factor milieu within the prostate, ultimately driving progressive enlargement in BPH. Beyond its direct androgenic drive, SRD5A2’s function in BPH may be further influenced by age-related changes in hormone levels and shifts in paracrine and autocrine signaling within the prostate microenvironmen^26,27. These changes can alter the balance between proliferation and apoptosis, favoring continued growth. In sum, SRD5A2 is central to the local generation of DHT in the prostate and is thereby a critical mediator of the hyperplastic changes that characterize BPH.

SRD5A2 Targeting Within the Multifactorial Treatment Landscape of BPH

While SRD5A2 is critical in the pathogenesis of BPH, it is well accepted that BPH and LUTS are multifactorial conditions influenced by smooth muscle tone, detrusor and neurological function, inflammation, and systemic metabolic factors (PMID: 19002119). Symptom severity correlates only modestly with prostate size, and bothersome symptoms such as nocturia or urgency often persist despite prostate volume reduction (PMID: 16530611). These complexities underscore the need for diverse therapies tailored to patient heterogeneity. Within this broader context, 5ARIs reduce intraprostatic DHT, decrease prostate volume, and lower long-term risks of progression (PMID: 9475762). Thus, SRD5A2 inhibition should be viewed as a disease-modifying therapy, complementing α-blockers (rapid symptom relief via smooth muscle relaxation and other strategies addressing inflammatory or metabolic drivers (PMID: 18036719, 16608892). This highlights opportunities for precision approaches by using molecular or clinical markers to identify patients most likely to benefit, and for combination regimens (e.g., α-blockers plus 5ARIs) that address multiple mechanisms simultaneously (PMID: 14681504). In general, while BPH/LUTS is inherently multifactorial, SRD5A2 targeting remains a clinically relevant and well-defined component of the treatment landscape, particularly in patients with enlarged prostates and androgen-driven disease biology.

SRD5A2 in Prostate Inflammation

The prostate is considered an immune-competent organ, characterized by the presence of a complex intraglandular immune system, a urinary/genital microbiome and the prevention of autoimmune reactions towards self-antigens(citations)²⁸. Chronic inflammation in the prostate is associated with altered SRD5A2 expression, leading to imbalanced androgen metabolism and dysregulated DHT synthesis²⁹. In a prostate with BPH, there is increased collagen deposition and infiltration of inflammatory mediators, such as T cells and macrophages, resulting in a chronic inflammatory status within the prostate. Elevated inflammation results in NF-kB activation, which has been demonstrated to stimulate expression of SRD5A2, AR, and AR-V7.¹¹ Chronic prostatic inflammation has been linked to alterations in androgen metabolism, including dysregulation of SRD5A2 expression²⁹. Increased expression of a network of pro-inflammatory activating protein-1 transcription factor/chemokine, including c-JUN, c-FOS, FOSB, cyclin D1, c-Myc, HB-EGF, MMP1, IL-6, and IL-8 is associated with symptomatic BPH³⁰. Chronic inflammation in the prostate also activates the NF-κB signaling, which can paradoxically upregulate SRD5A2 expression, leading to increased DHT production and AR signaling³¹. In retrospective cohort studies, taking TNF-α inhibitors were found having a shrinking effect on the prostate, suggest that TNF-α inhibitors may impede prostate growth^32,33.

Patients with chronic prostatic inflammation could be considered at risk of BPH development and progression. One of the key mechanisms driving these changes is obesity-associated inflammation, which has been shown to induce DNA methylation of the SRD5A2 promoter, effectively silencing its expression³⁴. Clinical studies have observed that higher body mass index (BMI) is correlated with increased SRD5A2 methylation and reduced protein expression, explaining why obese individuals with BPH often experience more severe urinary symptoms and show a diminished response to 5ARIs³⁵. The presence of prostatic inflammation might even alter 5-ARIs activity. In particular, increasing age and rising levels of inflammatory mediators (TNFα, nuclear factor-κB (NF-κB), and IL-6) can modify the activity of the enzyme DNA methyltransferase 1, which in turn regulates the expression of SRD5A2, the target of these medications³⁶. This various pattern of SRD5A2 regulation—being upregulated in some inflammatory conditions and epigenetically silenced in others—may be associated with heterogenous inflammatory microenvironment and contributes to treatment resistance to 5ARIs.

Structure, expression, and distribution of SRD5A2

Size, domain, and structure

Human SRD5A2 gene locates on chromosome 2, band p23, consists of five exons and four introns and its full-length protein SRD5A2 encodes 254 amino acids with a molecular weight of approximately 29.5 KD^14,26,37 (Fig. 1A). SRD5A2 functions as an integral membrane protein, highly expressed on the endoplasmic reticulum membrane. There are seven transmembrane helices in SRD5A2 interconnected with six loops. These alpha-helix transmembrane domains in SRD5A2 provide a large internal cavity to support substrate binding³⁸. X-ray crystallography study reported a dual-steric ligand NADP-dihydrofinasteride that occupies two distinct substrate binding pockets within the internal activity during SRD5A2 catalysis³⁸ (Fig. 1B). Two key amino acid residues, E57^TM2 and Y91^TM3 in SRD5A2, were identified for testosterone catalysis and finasteride and dutasteride inhibition³⁸ (Fig. 2A).

Fig. 1. The gene, structure, and distribution of SRD5A2.

(A) Genomic structure of SRD5A2. The horizontal line represents its genomic entire length; exons and UTRs are indicated by purple and orange boxes, respectively. The distribution of three genetic polymorphisms is indicated, respectively. Silencing methylation on the CpG island of the SRD5A2 promoter is schematically represented. (B) Crystal structure of SRD5A2 from PDM entry 7BW1 colored variably by domains³⁸. Seven transmembrane domains and NADPH binding pocket are labeled, respectively. (C) The expression profile of SRD5A2 in human tissues. The top fifteen organs with the highest SRD5A2 expression are indicated in the bar figure. The results are based on the analysis of GTEx Consortium⁴⁶ (available at https://www.gtexportal.org/home/gene/SRD5A2). (D) The expression profile of SRD5A2 in the single cell type clusters were visualized by a UMAP plot. The results are based on the single cell RNA sequencing resource of the Human Protein Atlas (available at https://www.proteinatlas.org/search/srd5a2 ). LE: luminal epithelial cell, HE: Hillock epithelial cell, CE: Club epithelial cell, BE: basal epithelial cell, SM: smooth muscle cell, Leu: leucocyte, Fib: fibroblast, Endo: endothelial cell.

Fig. 2. The enzymatic function of SRD5A2.

(A) Schematic model of SRD5A2 enzymatic reaction of converting testosterone (T) to dihydrotestosterone (DHT) with the hydrolysis of nicotinamide adenine dinucleotide phosphate (NADPH). Key residues on SRD5A2 for the formation of hydrogen bonds (drawn as dash lines) are also indicated. (B) The role of SRD5A2 in various androgen biosynthesis pathways. In some steps SRD5A2 may convert the same substrates as SRD5A1, but two 5α reductases differ in kinetic properties and are expressed in a tissue-specific fashion. Thus, some substrates are preferred by either SRD5A1 or SRD5A2 depending on specific situations.

Genetics: mutations and polymorphisms

More than 100 somatic mutations and polymorphisms have been reported in SRD5A2 gene, and many of which have a significant impact in SRD5A2 protein stability and enzymatic activity. Study identified 451 cases of 5α-reductase type 2 deficiency in the literature from 48 countries, which carrying 121 different allelic variants in the SRD5A2 gene, and most are missense mutations³⁷. 46 variants in SRD5A2 have been functionally investigated, and 42 out of 46 are non-synonymous allelic variants within exons 1–5³⁷. Somatic gene polymorphisms in SRD5A2 are also commonly studied. The three most reported polymorphisms in BPH patients are V89L (rs523349), A49T (rs9282858), and various length of thymine-adenine (TA) repeats³⁹. T allele in rs9282858 and shorter TA repeats are associated with higher SRD5A2 enzymatic activity and increased risk of BPH²¹. Such genetic variants may influence individual responsiveness to 5α-reductase inhibitors (5ARIs). For example, patients carrying high-activity alleles may achieve greater prostate volume reduction with therapy, whereas those with low-activity alleles may derive minimal benefit. Incorporating genetic screening into clinical decision-making could help identify patients most likely to respond to SRD5A2-targeted interventions. In addition, although the promising progress, limited number of patients. Therefore, more studies with larger cohorts are needed to further validate .

Epigenetics

Epigenetic modulation, specifically DNA hypermethylation at the promoter region of the SRD5A2 gene, leads to gene silencing and downregulation of SRD5A2 protein expression^40,41. This promoter region contains a heavily populated CpG dinucleotide that can potentially be methylated (Fig. 1A). Approximately 30% of BPH specimens exhibit promoter methylation, corresponding with low intraprostatic SRD5A2 levels⁴⁰. Decreased SRD5A2 expression in BPH tissues may contribute to the reduced efficacy of 5-ARI therapy in certain patient populations, yet the mechanism underlying SRD5A2 downregulation remained unelucidated. The study utilizing a comprehensive molecular investigation of BPH defined a methylation signature for BPH that included 696 differentially methylated CpGs in promoter regions, found negative correlation between promoter methylation and gene expression, and hypermethylation is the dominant signal across all genomic regions⁴². Furthermore, a multivariate logistic regression analysis on 96 prostate samples derived from transurethral resection prostatectomy (TURP) samples suggests that BMI and age are two factors with significant association with DNA methylation at the SRD5A2 promoter region, thus leading to reduced SRD5A2 protein expression³⁵. Besides BMI and age, inflammatory mediators can also affect methylation status in the SRD5A2 promoter. In human prostatic stromal cells cultured with macrophage-conditioned media, SRD5A2 promoter methylation was significantly elevated, suggesting that proinflammatory mediators are associated with the SRD5A2 hypermethylation at the promoter region⁴³. For instance, TNF-α and IL-6 regulate the SRD5A2 promoter methylation by activating DNA methyltransferase I (DNMT1) in vitro and in BPH tissue samples²⁶. DNMT1 is abundantly expressed in the developing prostate, and its expression is upregulated in castrated mice treated with testosterone⁴⁴. Elevated DNMT1 activity is reported to promote SRD5A2 promoter methylation, which leads to SRD5A2 gene silencing and SRD5A2 protein downregulation³⁶. Together, these interdisciplinary studies collectively support that hypermethylation at the SRD5A2 promoter region is strongly associated with downregulation of SRD5A2 expression, and multiple factors including BMI, age, and inflammation can contribute to this epigenetic regulation on SRD5A2. Patients with methylation-induced SRD5A2 loss are less likely to benefit from 5ARI therapy, as androgen conversion to DHT is already diminished. In these cases, alternative or adjunctive approaches, such as selective estrogen receptor modulators to counteract estrogenic pathway activation, may provide greater symptomatic and structural benefit.

Distribution of SRD5A2

Human SRD5A2 gene is predominantly expressed in sex hormone-sensitive tissues including prostate, testis, and seminal vesicles in men, vagina, fallopian tube in women, and other organs like liver, bladder, and hair follicle (Fig. 1C)^14,26,45. As an androgen-dependent tissue with remarkable experimental properties, prostate has the highest SRD5A2 mRNA expression according to tissue-specific transcriptomic datasets from the Genotype-Tissue Expression (GTEx) Consortium⁴⁶ (Fig. 1C). While SRD5A2 is the predominant, if not exclusive, isozyme in the healthy human prostate, SRD5A1 is undetectable, suggestive of the sole responsibility of SRD5A2 to supply DHT for prostate growth and maintenance⁴⁷. Single-cell RNA sequencing data showed that SRD5A2 expression is enriched in stromal cells, with lower expression in epithelial and immune cells (Fig. 1D).

SRD5A2 activity and expression display significant population variance due to differences in genetic polymorphisms, hormonal factors, and environmental influences. Hispanic, African and African American populations exhibit a higher frequency of the V allele in V89L polymorphism, which may contribute to a higher prevalence of prostate cancer^48,49, while the East Asian population predominantly carries the L allele that displays a lower enzymatic activity and potentially contributes to a reduced risk of^50,51. The T allele in A49T and the V allele in V89L polymorphism are known to be associated with increased enzymatic activity and higher DHT production in vitro⁴⁸. These two polymorphisms contribute to the majority of observed ethnicity differences in SRD5A2 activity, as well as risk of developing BPH and prostate²¹.

Function of SRD5A2

Enzymatic function of SRD5A2

SRD5A2 in prostate irreversibly converts testosterone into DHT to supply intraprostatic androgen in a β-nicotinamide adenine dinucleotide 2´-phosphate (NADPH)-dependent manner⁵². SRD5A2 reduces the Δ^4,5 carbon-carbon double bond in testosterone to carbon-carbon single bond in DHT with the hydride donor NADPH as shown in the Fig. 1B. X-ray crystallography-based study proposed an in silico docking structure of SRD5A2 with NADPH and testosterone where the A ring in testosterone is positioned in parallel to the nicotinamide ring in NADPH with an estimated distance of 2.5 Å between the Δ^4,5 double bond of testosterone and the 4-pro-(R)-hydride of NADPH³⁸. Specifically, Glu57 and Tyr91 residues of SRD5A2 formed hydrogen bonds with the C-3 carbonyl group in testosterone, and this proposed configuration favors the hydride transfer from NADPH and enolization of Δ^4,5 double bond³⁸.

Role of SRD5A2 in AR signaling pathway

Androgens constitute an indispensable component of the pathophysiology of BPH. While both can readily bind to AR, DHT and testosterone are believed to exert different physiological functions. SRD5A2 is an essential upstream regulator of AR signaling by producing the primary binding ligand DHT to activate AR in prostate. AR belongs to the type-I class nuclear hormone transcription factor family, which is typically held at the inactivated form in the cytoplasm where it binds to heat shock proteins (HSPs). HSPs function as molecular chaperones to maintain the AR protein structure and prevent misfolding⁵³. Excessive activation of AR signaling can overstimulate the differentiation and proliferation of prostate cells and lead to male urinary system diseases^11,54. When SRD5A2 functions in conjunction with HSD17B6 in the backdoor pathway which also produces DHT, AR signaling pathway is overactivated and leads to multiple androgen-related diseases, such as acne, androgenetic alopecia, prostate cancer, etc.⁵⁵. In addition, AR signaling exerts a reciprocal effect on its upstream regulators, SRD5A1 and SRD5A2. Intriguingly, while both SRD5A1 and SRD5A2 are direct AR target genes⁵⁶, they are differentially regulated by AR signaling pathway in the context of prostate cancer: activated AR induces SRD5A1 expression while repressing SRD5A2 expression⁵⁷. Developing a comprehensive understanding of the AR signaling pathway and its differential feedback mechanisms on SRD5A1 and SRD5A2 will be informative to advance clinical treatments for androgen-related diseases.

Alternative signaling pathway

Increasing evidence supports a role for estrogens in the pathogenesis of BPH. Estrogen receptor (ER) and AR share a similar design of structural and functional domains. ERα and ERβ are encoded by two distinct genes located on different chromosomes. The two ER subtypes have the same arrangement of functional domains with the most conserved region being the DNA binding domain (97% identity), consistent with the receptors binding to similar DNA response elements¹³. While the localization of ER remains controversial in literature, it is generally accepted that ERα is generally expressed in the stroma compartment, and ERβ is expressed in the basal and luminal cells of the epithelium^58,59. Estrogens exert their effects on target gene expression via binding to specific intracellular ERs, which function as hormone inducible transcription factors. In the 30% of BPH patients with low SRD5A2 expression, the estrogenic pathway is activated via the upregulation of aromatase and phosphorylated ERα (pERα)⁶⁰. In addition, TNF-α upregulates both aromatase and pERα. Aromatase is a key enzyme involved in the conversion of testosterone to estradiol and plays a crucial role in the elevation of androgen/ estrogen (testosterone/estradiol: T/E) ratio as men age⁶¹. Once testosterone is converted to estradiol, the ER signaling pathways regulate prostate growth upon binding to estradiol⁵⁸.

Development of 5ARIs

Structure and Mechanism of Action of 5ARIs

Both finasteride and dutasteride are 4-azasteroids, characterized by a nitrogen atom replacing the carbon at position 4 of the steroid nucleus (Fig. 3A)¹⁴. The steroid ring of finasteride includes a lactam (cyclic amide) group at position 3 and a tert-butyl carbamate substituent at position 17β relatively smaller than the bulky side chain of dutasteride, which contributes to its binding to the hydrophobic cavity of SRD5A2, forming a stable NADP-DHF adduct that blocks substrate access and thus selectively inhibit SRD5A2 and reduce serum DHT level (Fig. 3B)³⁸. In addition, the 2,5-bis(trifluoromethyl)phenyl group at position 17β of dutasteride, significantly increasing its bulkiness and hydrophobicity by creating strong van der Waals interactions with the enzyme’s active site, which contributes to enhancing its reversible binding to both SRD5A1 and SRD5A2⁶². Furthermore, the hydrophobic trifluoromethyl groups on the phenyl ring of dutasteride’s side chain also improve dutasteride’s membrane permeability and possibly contribute to different metabolisms thus prolonging its half-life compared to finasteride. The structural differences lead the distinct pharmacological profiles and isoenzyme selectivity: Dutasteride exhibits broader affinity for SRD5A isoenzymes, achieving near-complete DHT suppression (up to 94%) compared to finasteride’s 70% reduction in serum DHT, and reduces PSA level as well⁶³.

Fig. 3. The structure and Mechanism of Action of 5ARIs.

(A) The chemical structure of testosterone, finasteride, and dutasteride. (B) Mechanism of Finasteride inhibition of 5α-reductase with NADPH-DHF intermediate^38,100.

Pharmacokinetics and pharmacodynamics of 5ARIs

Both finasteride and dutasteride are administered orally with a mean bioavailability of approximately 60–80% from a 5 mg dosage of finasteride and a 0.5 mg dosage of dutasteride, which are widely distributed into peripheral tissues, including the prostate gland, and cross the blood-brain barrier, potentially altering neurosteroid synthesis^64,65. 5-ARIs undergo two phase metabolisms. In phase I, both finasteride and dutasteride are extensively metabolized by the hepatic cytochrome P450 enzymes. The biotransformation during this step majorly involves CYP3A4-mediated hydroxylation and oxidation⁶⁶. Finasteride is converted to ω-hydroxyfinasteride and dutasteride is converted to 6-β-hydroxy-dutasteride. These major metabolites have comparable activity to that of finasteride and dutasteride. Phase II metabolism of 5ARIs involves glucuronidation catalyzed by the enzyme superfamily uridine diphosphoglucuronosyltransferase (UGT). Similar to steroid hormones, this step of metabolism renders the lipophilic 5ARI metabolites more water-soluble and thus promotes inactivation and elimination via urine or feces⁶⁷. 32–46% of the finasteride is excreted in the urine, with the remaining 51–64% excreted in feces within a seven-day period. The elimination of dutasteride is also in similar ratios. The half-life of finasteride is 4.7 to 7.1 hours in healthy young male volunteers and is independent of dose⁶⁸. The half-life of dutasteride is up to 5 weeks, significantly longer than finasteride, allowing for sustained suppression of DHT even after discontinuation of administration⁶⁴. Finasteride and dutasteride exert their therapeutic effects by inhibiting the enzyme 5α-reductase. Finasteride selectively inhibits SRD5A2, reducing intraprostatic DHT by ~70%, while dutasteride inhibit both SRD5A1 and SRD5A2, and achieves >90% suppression of DHT, leading to more pronounced prostate volume reduction and symptom relief in BPH⁶⁹.

Adverse effects

5ARIs are considered well-tolerated medications, with the most adverse effects reported as mild and transient. However, the adverse effects have led to debate around their use owing to the possible onset of post-finasteride syndrome (PFS)⁷⁰. PFS is defined as the persistence of common adverse effects: emotional, psychological, physical and sexual. Symptoms include sexual effects (ED, decreased libido, chronic testicular pain and penis shrinkage), physical effects (gynaecomastia, penis shrinkage, penile curvature, testicular reduction, muscle atrophy and dry skin) and psychiatric symptoms (depression, anxiety, suicidal thoughts and insomnia). The definition of PFS extends to patients in whom the symptoms persist months or even years after treatment discontinuation^70,71. Clinical trials report a 5–9% incidence of de novo erectile dysfunction (ED) in patients on 5ARIs, with meta-analyses confirming a 1.5- to 2.6-fold increased risk compared to placebo⁷². Meanwhile, in a recent pooled data analysis composed of over 2 million patients taking 5ARIs, no evidence of an association between 5-ARI use and the risk of depression or suicide was found⁷³.

Clinical Significance of Targeting SRD5A2

Implications for BPH Therapy

Targeting SRD5A2 with 5ARIs finasteride and dutasteride has been a cornerstone of BPH therapy, reducing prostate volume and improving lower urinary tract symptoms (LUTS)²³. In the Medical Therapy of Prostatic Symptoms (MTOPS) study, long-term monotherapy of either 5ARI or alpha-blockers leads to significant LUTS improvement, with a reduction in total prostate size by 25%⁷⁴. The combination of 5ARI and alpha-blockers reduced the risk of overall LUTS progression by 66% compared to doxazosin or finasteride monotherapy¹⁰. Additionally, not only does the general growth rate of the total prostate may depend on the expression of SRD5A2, but the growth rate of different prostate zones also varies and affected differently by 5ARI therapy. Utilizing MRI data for accurate prostate measurement, it has been shown that the 5ARI treatment significantly reduces the growth rate of the transition zone of the prostate⁷⁵. The transition zone located in the anterior and central part of the gland is made up of majorly compressed fibromuscular tissue and is the source of about 20% prostate cancer and only part of the prostate where BPH occurs^76,77. The difference in 5ARI effect on growth rate of transition zone may have a regulatory underpinning, as some subgroups of the prostate cells are more SRD5A2 expressing or more affected by other factors such as BMI, inflammation, and non-androgenic pathways than others^12,34. Understanding the distribution of SRD5A2 provides valuable insights into its physiological functions under the normal and diseased conditions.

Selective estrogen receptor modulators (SERMs) in clinical trials

Epigenetic silencing or genetic variations of SRD5A2 have been shown to shift prostate metabolism toward increased ER signaling​¹². This shift in hormonal regulation implies that SERMs, such as raloxifene, could provide therapeutic benefits in men who are resistant to 5ARIs therapy. Preclinical data show that patients with SRD5A2 methylation have higher ERα expression, making them more likely to benefit from dual therapy with finasteride and raloxifene compared to 5ARI monotherapy¹²​. Clinical trials have explored the combination of 5ARIs with SERMs to target both androgenic and estrogenic signaling in BPH and prostate cancer⁷⁸​. Ongoing trials are assessing whether biomarker-driven selection of BPH patients with SRD5A2 deficiency improves treatment response to combination therapy⁷⁹. The rationale behind this approach is based on findings that SRD5A2-deficient prostate tissues exhibit increased aromatase activity, leading to higher estradiol levels and enhanced estrogenic signaling, which contributes to prostate cell survival and proliferation¹². Targeting both androgenic and estrogenic pathways might provide superior clinical benefits in men who fail to respond to traditional androgen-targeted therapies​.

Applications in Prostate Cancer

As a potential anti-prostate cancer target, the effects of SRD5A2 on prostate cancer susceptibility, and the use of 5ARIs finasteride and dutasteride is drawing increasing attention⁸⁰. Prostate cancer resistance to castration occurs because tumors acquire the metabolic capability of converting precursor steroids to DHT, promoting signaling by the AR and the development of castration-resistant prostate cancer (CRPC)⁵². Despite androgen deprivation therapy (ADT), which aims to lower systemic androgen levels, prostate cancers adapt by increasing intratumoral androgen synthesis, allowing cancer cells to bypass androgen depletion and continue proliferating⁸¹. Adrenal-derived androstenedione (AD) is the preferred substrate over testosterone (T) for 5α-reductase expressed in metastatic CRPC, bypassing T as an obligate precursor to DHT⁸². Essential for resistance, DHT synthesis requires enzymatic reactions by SRD5A and other isoenzymes⁸³. SRD5A2 plays a crucial role in prostate cancer progression, particularly in the development of CRPC. By catalyzing the conversion of testosterone into DHT, SRD5A2 sustains AR signaling, which is essential for prostate cancer cell growth and survival⁸⁴. Progression to CRPC is accompanied by increased expression of SRD5A1 over SRD5A2, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT⁸⁵. On the other hand, ADT induces the upregulation of SRD5A3 within as little as three months, leading to therapy resistance and CRPC⁸⁶. These findings highlight the limitations of single-enzyme inhibition strategies and suggest that future therapeutic approaches should target multiple steroidogenic pathways to effectively suppress AR-driven tumor progression and improve prostate cancer treatment outcomes.

Used as a chemopreventive strategy to reduce the risk of prostate cancer, two large randomized controlled trials observed a 23–25% lower incidence of prostate cancer compared with placebo. The overall reduction was driven mostly by lower-grade tumors, while an unexpected increase in high-grade cancers appeared in the 5ARI groups^87–89. However, another study with long-term follow-up found no significant association between 5ARI use and either high-grade (HR 0.97; 95% CI, 0.64–1.46) or lethal prostate cancer (HR 0.99; 95% CI, 0.58–1.69) after multivariate adjustment⁸⁰. In a clinical trial of abiraterone, 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while Δ(4)-abiraterone (D4A) concentrations rose, which has greater anti-tumor activity, showing that dutasteride effectively blocks production of a tumor-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism⁹⁰. An ongoing Phase 3 study named The Finasteride in Active Surveillance (AS) for Men with Low- and Intermediate-Risk Prostate Cancer (FINESSE) is utilizing a contemporary cohort, seeks to assess whether the addition of finasteride to AS improves adherence in men with low- and intermediate-risk prostate cancer, evaluate the tolerability and compliance of finasteride within an AS regimen, determine whether finasteride reduces disease progression, ultimately lowering the need for radical treatment⁹¹.

Since genetic polymorphisms of SRD5A2 can alter SRD5A2 catalytic activity or affect an individual’s response to 5ARIs inhibitors, variations in SRD5A2 function and inhibitor pharmacodynamics have also been investigated across different populations with diverse racial backgrounds³⁹. Study showed that an increased risk of prostate cancer in African American and Hispanic men who carried the high SRD5A2 activity A49T variant, others demonstrated that SRD5A2 rs9282858 and rs523349 polymorphism may be a susceptible factor to prostate cancer^92,93. In addition, studies found that differentiated methylated SRD5A2 strongly correlated to prostate cancer^94,95. Specifically, CRPC patient demonstrated higher SRD5A2 methylation in the whole promoter region compared with normal benign prostatic tissue, and methylation in the CpG island of SRD5A2 promoter region is tightly associated with better survival for CRPC patients treated with ADT⁹⁵. Utilizing methylation pyrosequencing of 86 prostate cancer patients’ plasma cell-free DNA samples, another study found that increased DNA methylation of SRD5A2 and CYP11A1 may play a role in biochemical recurrence after patients’ prostatectomy⁹⁶. Overall, targeting SRD5A2 via epigenetic manipulations may be a promising strategy to treat BPH, CRPC, and other androgen-related diseases.

Applications in Other Androgen-Related Diseases

The use of 5ARIs has been extended to androgen-driven dermatological conditions such as androgenic alopecia (AGA), hirsutism, and acne⁹³. Finasteride is approved by the Food and Drug Administration for the treatment of male AGA. There is no clear evidence to support the use of dutasteride in male AGA. In female AGA, the effectiveness of dutasteride and finasteride is still under debate⁹⁷. In androgenic alopecia, SRD5A2 activity in scalp hair follicles leads to excess DHT production, causing hair follicle miniaturization, shortened anagen (growth) phase, and eventual hair loss. Clinical studies have demonstrated that finasteride reduces scalp DHT levels by approximately 60% and significantly slows hair loss progression, with some patients even experiencing hair regrowth⁹⁸. However, treatment discontinuation often results in DHT rebound and hair loss recurrence, emphasizing the need for long-term therapy for sustained benefits. On the other hand, 5ARIs have been effective in reducing excessive hair growth by lowering DHT production⁹⁸, and reducing sebum production to potentially treat androgen-related skin conditions^84,99.

Future perspectives

Despite their widespread use, 5ARIs have shown only partial success in improving long-term outcomes for BPH. Several limitations are well recognized: (i) the delayed onset of action compared to α-blockers, leading to slower symptom relief; (ii) only modest correlation between prostate volume reduction and patient-reported LUTS improvement; (iii) persistence of bothersome symptoms such as nocturia or urgency despite effective prostate shrinkage; and (iv) significant interpatient variability in response. This variability is influenced by genetic polymorphisms in SRD5A2, epigenetic silencing through promoter methylation, and metabolic dysfunction. Together, these factors highlight why previous attempts to optimize 5ARI therapy have produced only incremental gains in clinical practice.

Studies of BPH samples from both the MTOPS trial and institutional cohorts suggest that SRD5A2 may serve as a valuable predictive marker for finasteride response. Prior to initiating therapy, assessing SRD5A2 methylation in peripheral white blood cells (WBCs) or using ferumoxytol-enhanced prostate MRI to evaluate inflammation could provide non-invasive approaches to predict treatment response. Developing non-invasive biomarkers to stratify patients who are likely to exhibit 5ARI resistance is critical for advancing our understanding of the clinical implications and for guiding more personalized treatment strategies.

SRD5A2 expression is influenced by inflammation, being upregulated in some inflammatory conditions while epigenetically silenced in others, contributing to heterogeneous treatment responses in patients with BPH and prostate cancer. As inflammation and androgen metabolism are closely interconnected, future therapies should aim to simultaneously target inflammatory pathways and androgen signaling. Combining anti-inflammatory agents with androgen-targeted therapies could enhance treatment efficacy, especially in patients resistant to 5ARIs.

Despite their ability to reduce prostate size and alleviate LUTS, 5ARIs have shown limited long-term success in some patients, with resistance and treatment failures being particularly common in inflamed prostates. Several factors explain these limitations, including SRD5A2 genetic polymorphisms, epigenetic silencing through methylation, chronic inflammation sustaining local androgen production, and an androgen-to-estrogen shift, often worsened by obesity and metabolic dysfunction. Clinically, these mechanisms manifest as delayed onset of symptom relief, persistence of bothersome LUTS such as nocturia despite effective prostate shrinkage, and highly variable patient responses. Emerging evidence also highlights ER activation and epigenetic regulation of SRD5A2 as contributors to treatment resistance. Incorporating SERMs into treatment could offer a more tailored approach, especially for patients with epigenetically silenced SRD5A2. This combination strategy, including SERMs (such as raloxifene), 5ARIs, and anti-inflammatory agents, may become a future standard for patients with SRD5A2-deficient prostate disease, pending results from ongoing clinical trials.

Taking together, these proposed biomarker-driven and combination strategies are intended to directly address these historical limitations. For example, profiling SRD5A2 genetic variants and promoter methylation could enable stratification of patients most likely to respond to 5ARI therapy, providing a precision medicine framework rather than a one-size-fits-all approach. In parallel, combination regimens, such as 5ARIs with α-blockers, SERMs, or anti-inflammatory agents, are designed to overcome non-androgenic mechanisms of LUTS, including smooth muscle hyperactivity, estrogen-driven remodeling, and chronic inflammation. In this way, these strategies go beyond incremental extensions of existing therapy, instead representing targeted solutions to the multifactorial biology of BPH. By integrating molecular profiling with mechanism-based treatment combinations, SRD5A2-targeted therapy could achieve greater clinical relevance and more durable improvements in patient outcomes.

Beyond BPH, SRD5A2 has also been implicated in prostate cancer and androgenic alopecia, although the therapeutic goals and patient populations differ substantially. In BPH, the primary objective is relief of LUTS and prevention of progression. In prostate cancer, particularly castration-resistant disease, SRD5A2 inhibition aims to limit intratumoral DHT synthesis to suppress tumor growth. In androgenic alopecia, the goal is preservation of hair follicles by reducing scalp DHT levels. These differences underscore the importance of context-specific application of SRD5A2-targeted strategies rather than a one-size-fits-all approach.

In summary, SRD5A2 remains a key therapeutic target in prostate cancer management, particularly in early-stage tumors and select cases of CRPC. While 5ARIs alone have shown limited efficacy in advanced disease, combination therapies that target multiple steroidogenic pathways alongside AR signaling offer promising avenues for improving treatment outcomes. Future research should prioritize identifying patient subgroups most likely to benefit from SRD5A2 inhibition, as well as developing more potent inhibitors capable of overcoming intratumoral androgen synthesis adaptations. With continued advancements in precision oncology and combination therapy approaches, targeting SRD5A2 and related steroidogenic enzymes could lead to more effective and durable therapies for prostate cancer, including CRPC.

Conclusions

SRD5A2 plays a central role in androgen metabolism and prostate health, making it a critical target for managing BPH and prostate cancer. However, its expression is influenced by genetic polymorphisms, epigenetic silencing, and inflammation, contributing to variable responses to 5ARIs. Personalized approaches, such as assessing SRD5A2 methylation or imaging prostate inflammation, could help predict treatment response and guide therapy selection. Combining 5ARIs with anti-inflammatory agents or SERMs may further improve outcomes, particularly for patients with inflammation-driven metabolic shifts. In prostate cancer, targeting SRD5A2 alongside other steroidogenic enzymes could enhance treatment efficacy, especially in CRPC. Overall, integrating genetic, epigenetic, and metabolic profiling into SRD5A2-targeted strategies holds promise for more personalized and effective therapies in prostate-related diseases.