Beyond the Prostate: A Visionary Study on Ocular Impacts of Benign Prostatic Hyperplasia Drugs

Introduction

Benign prostatic hyperplasia (BPH) is a common urologic condition encountered in aging men with common symptoms such as difficulty voiding, nocturia, and increased urinary frequency. Studies have demonstrated modest expansion in the prostate with increasing age, with a prevalence of 50% of men over age 50, 70% of men between ages 60 and 69, and 80% in those over 70 years of age for BPH in the United States. ¹ With BPH complications such as urinary retention and urinary tract infections, pharmacologic interventions such as alpha-1 antagonists and 5-alpha reductase inhibitors are indicated to either increase urinary flow or to reduce androgens involved in prostate growth, respectively. Alpha-1 antagonists and 5-alpha reductase inhibitors are the predominant pharmacological agents for the treatment of BPH that provide favorable tolerability and efficacy in improving urinary symptoms. ² While these drugs offer favorable outcomes in BPH patients, it is imperative for ophthalmologists and urologists to exercise caution and be cognizant of the possible adverse ocular effects before prescribing them.

In addition to impacting the prostate, alpha-1 antagonists and 5-alpha reductase inhibitors such as tamsulosin and finasteride have been shown to be linked with the occurrence of intraoperative floppy iris syndrome (IFIS). ³ This syndrome is characterized by small pupils that exhibit poor responses to dilation due to stretches that occur during cataract surgery. ³ Tamsulosin, an α1A/α1D selective α1-antagonist, has been shown to be dominant in the iris dilator muscle, which can explain the cause for IFIS.^4,5 Interestingly, IFIS has been shown to occur in selective alpha-1 antagonists, but nonselective alpha-1 antagonists have been shown to not induce IFIS. ⁶ Further, among selective alpha-1 antagonists, studies have shown that alfuzosin, terazosin, and doxazosin do not have as much specificity as tamsulosin does to certain subtypes of alpha-1 receptors.^7,8 Clinical trials assessing the frequency of IFIS among different alpha-1 antagonists can aid future research in understanding the relationship between alpha-1 antagonists and IFIS.

In addition to IFIS, other ocular adverse effects have been reported to be associated with tamsulosin and finasteride intake. Retrospective cohort studies in Spain found a higher association between tamsulosin and ocular symptoms such as rebound uveitis and macular edema. ⁹ While these findings shed light on the connection between tamsulosin and broader ocular symptoms, our study endeavors to provide an exploration of the entire spectrum of ocular effects associated with tamsulosin usage, which can highlight the need for further in-depth investigation.

Beyond tamsulosin, the possibility of ocular manifestations resulting from 5-ARIs remains conceivable. Animal studies have demonstrated noteworthy evidence of tear deficiency and inflammation in the lacrimal gland after administration of finasteride, potentially leading to the development of dry eyes. ¹⁰ Notable ocular abnormalities such as macular holes and foveal cavitation were identified in a few studies among patients taking 5-ARIs. ¹¹ In these investigations, constraints within the study designs may impede researchers from making complete clarifications on the specific impacts of 5-ARIs on the lacrimal glands and the retina, emphasizing the necessity for additional research.

By analyzing real-world data from the FDA Adverse Event Reporting System (FAERS) database, we explored potential avenues for future research and investigations regarding the relationship between alpha-1 antagonists, 5-ARIs, IFIS, and other ocular effects. This pharmacoepidemiology study aims to assess the relative frequency of ocular side effects linked to alpha-1 antagonists and 5-ARIs, enhancing our understanding of their overall safety profile.

Materials and Methods

Statistical analysis and signal detection

We provided a comprehensive count of adverse ocular effects associated with tamsulosin, finasteride, doxazosin, terazosin, alfuzosin, and silodosin. Subsequently, authors independently reviewed all reported adverse events and classified the symptoms into appropriate ophthalmological categories (Fig. 1). To ensure thorough analysis of data and ease in table interpretation, combined symptoms were employed as the FAERS database presents similar symptoms (Fig. 2).

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FIG. 1.

Schematic Consolidation of Ocular Adverse Event Terms.

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FIG. 2.

Detailed Grouping of FAERS Ocular Adverse Event Terms. Individual terms were consolidated into combined symptom categories to account for overlapping adverse event reports within the FAERS database.

We employed specific methods to conduct a quantitative signal detection analysis and investigate the occurrence of symptoms within each category. A safety signal pertains to information regarding a potential side effect associated with a medication and typically arises when multiple reports indicate a suspected side effect. To identify such signals, we utilized four data mining algorithms: reporting odds ratio (ROR), proportional deployed ratio (PRR), empirical Bayes geometric mean (EBGM), and information component (IC). These algorithms enable the identification of adverse events due to a suspected drug that occur at a higher frequency in comparison to the remaining FAERS database. These data-mining algorithms analyze FAERS reports by comparing cases involving both the suspect drug and adverse reaction to reports featuring similar reactions linked to other drugs, different reactions associated with the suspect drug, and unrelated drug-event pairs. These algorithms utilized either chi-square tests (PRR) or confidence intervals (ROR, IC, and EBGM) to establish statistical significance. The statistical techniques employed in these methods have been extensively described and studied in prior literature.^15–18

In accordance with recommendations from prior studies, we established the criteria for identifying a positive signal based on the following parameters: PRR, ROR, IC, and EBGM, to demonstrate positive values, with higher values indicating stronger drug-adverse event associations. Additionally, algorithms such as ROR, PRR, and EBGM required a minimum case count to validate an association, with each suspected drug-adverse event pair satisfying the highest threshold of three reports required by PRR. ¹⁹ Further details on methodology, specific threshold values, and requirements for detecting significant drug-adverse event pairs are well described in previous studies. ¹⁹ All statistical analysis was conducted using SPSS Statistics Version 25.0 (IBM Corporation, Armonk, NY) and Microsoft Excel (Microsoft Corporation, Redmond, WA). The study was developed in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines.

Results

Between the first quarter of 2004 and the end of the third quarter of 2023, the FDA FAERS database revealed 11,439,756 unique adverse event reports. Out of 23,440 reports related to six BPH medications, 1,682 were associated with ocular outcomes. Tamsulosin dominated with 1,356 reports (80.67%), followed by finasteride with 180 reports (10.71%) (Tables 1 and 2). Doxazosin and terazosin collectively contributed 71 reports (4.22%), while alfuzosin and silodosin added 75 reports (4.46%) (Tables 3 and 4).

Among all analyzed reports, iris and cataract symptoms prevailed as the main ophthalmical adverse effects, accounting for 871 reports (51.78%). The second-highest category included visual and neurological changes, making up 503 out of 1,682 reports (29.90%). Additionally, retinal changes, such as macular edema, macular degeneration, and retinal detachment, constituted the third-highest prevalent category with 149 reports.

Significant positive signals were observed with tamsulosin, particularly in well-documented complications like cataract and iris issues. Iridocele showed the highest statistical significance (n = 65; PRR: 2066.0; ROR: 2079.5; EBGM: 737.03; IC: 9.53), while the second-highest significance was found in macular fibrosis (n = 15; PRR: 51.1; ROR: 51.16; EBGM: 48.94; IC: 5.61). Lacrimal (n = 23; PRR: 17.2; ROR: 17.2; EBGM: 16.96; IC: 4.08) and corneal pathologies (n = 17; PRR: 10.28; ROR: 10.3; EBGM: 10.2; IC: 3.35) also showed statistically significant associations with tamsulosin. Finasteride mirrored these findings, with iris and cataract symptoms being most significantly associated, followed by retinal symptoms like macular hole and retinal edema. Corneal and lacrimal gland pathologies showed significant associations with fewer reports.

Doxazosin and alfuzosin exhibit notable associations with floppy iris syndrome, with limited cases of ocular pathologies beyond the iris. Silodosin and terazosin, having the fewest reports, did not show significant associations in any symptoms according to the disproportionality analysis.

Discussion

Here, we conducted a pharmacovigilance study that examines the ophthalmological outcomes associated with the usage of alpha-1 antagonists and 5-ARIs. Alpha-1 antagonists facilitate smooth muscle relaxation in the prostate, promoting freer urine flow through the urethra. ²⁰ Finasteride, a 5-ARI, reduces prostate size to treat BPH-associated prostate growth. ²¹ While both drug classes are efficacious in treating BPH, they have been reported to be associated with IFIS and other ocular effects. In this study, we obtained comprehensive national-level figures on the incidence of adverse ophthalmological events. To assess the symptom significance, we employed disproportionality analysis and statistical measures. Through the data mining of FAERS, ocular adverse events such as IFIS, macular fibrosis, retinal degeneration, vitreous floaters, xerophthalmia, dacryocystitis, and orbital pathology can be quantified for frequency and drug-adverse event signal strength. Although other adverse ocular events are possible due to incomplete studies on the mechanism of alpha-1 antagonists and 5-ARIs, no other reports were deemed significant through statistical analysis of FAERS.

The exact mechanism by which tamsulosin leads to IFIS remains unknown, despite it being the most common cause of IFIS formation. ³ Chang et. al., in a retrospective and prospective study, suggest that tamsulosin has a high affinity for the α1A receptor, a dominant receptor of the iris. ²² Approximately 70% of α1 receptors in the prostate are of the 1A subtype, with far fewer in the peripheral circulation, allowing for tamsulosin to be uroselective. ²³ It can be theorized that selectivity of alpha-1 antagonists can impact the onset of IFIS, as nonselective alpha-1 antagonists such as bunazosin and other alpha subtype blockers induced IFIS at a significantly lower rate compared to tamsulosin. ⁶ Pharmacological investigations have also shown that tamsulosin binds to dopamine and serotonin receptors, in addition to alpha-receptors. ²⁴ Additional receptor-binding studies may help elucidate the pathogenesis of tamsulosin-induced IFIS, but further investigation through clinical trials is warranted given the lack of experimental validation in this study.

Tamsulosin does induce other adverse ocular effects in addition to IFIS. Our data findings revealed a positive signal for retinal detachment and tamsulosin, providing guidance for future investigations to explore any potential causal relationship. The findings from Bell et al. in their nested case-control study, investigating the associations between tamsulosin and serious ocular effects, align with our findings, as they observed a significant association for retinal detachment by using the odds ratio. ²⁵ On the other hand, retrospective cohort studies in Spain found similar incidence for retinal detachment between exposed and unexposed patients to tamsulosin, suggesting that tamsulosin intake may not substantially impact pupil dilation to the extent of causing retinal effects. ⁹ Additionally, it is noteworthy that intraocular pressure (IOP) remains significantly elevated after postoperative cataract surgery in individuals taking tamsulosin, a finding that aligns with our observations of a positive tamsulosin-IOP elevation from the FAERS database analysis. ²⁶ This is significant as raised IOP can lead to open-angle glaucoma, a chronic degeneration of the optic nerve. However, the mechanisms behind this association remain unclear and can be due to other factors or confounding variables such as preoperative administration of eyedrops. Dacryocystitis, inflammation of the lacrimal sac, has a rare association with tamsulosin, and there is only one case report that showed this finding. ²⁷ Furthermore, FAERS analysis has revealed positive drug signal findings, such as periorbital pain, which are associated with dacryocystitis. ²⁸ The limited number of studies on this drug-adverse event pair, coupled with positive signals from FAERS analysis, highlights the need for future research to conduct thorough investigations on this topic.

Although studies present findings related to tamsulosin, a literature review on all alpha-1 blockers and IFIS found that the relationship between other alpha-1 antagonists and IFIS is not well defined. ²⁹ A retrospective analysis reviewing patients using tamsulosin or doxazosin undergoing cataract surgery found that the incidence of IFIS remains high in doxazosin and tamsulosin compared to other alpha-1 blockers. ³⁰ This finding is further refined in a meta-analysis by Charziralli et al., where they found a large effect size of tamsulosin while also detecting a comparable effect size of doxazosin as potential risk factors for IFIS. ³¹ This finding is intriguing, as doxazosin is recognized as a nonselective alpha-1 antagonist, implying that selectivity may contribute to alpha-1 antagonist-mediated IFIS, but it may not account for the entire effect. For example, a retrospective case-control study by Santaella et al. found that iris dilator muscle thickness is thinner for tamsulosin patients when compared to a control group, perhaps shedding light on the pathophysiology of intraoperative floppy iris syndrome. ³² Regardless, future studies can bolster the causal relationship between alpha-1 antagonists and IFIS by incorporating covariates like age, diabetes, and other systemic drugs that may influence iris behavior. ³³

Tamsulosin has demonstrated prominent drug signals for retinal symptoms, orbital symptoms, and increased IOP, but these findings were not observed in other alpha-blocking medications. This suggests that the decreased reporting for other alpha-1 antagonists could either be attributed to genuine decreased occurrences of drug-adverse event pairs or the possibility of underreporting. Interestingly, Bell et al. did not find associations of endophthalmitis, retinal detachment, and lens dislocation with other alpha-blocking medications, indicating potential variation of effects among different alpha-1 antagonists. ²⁵ Pharmacologic studies by Li et al. found that doxazosin decreased inflammatory cytokines and contributed to the preservation and treatment of retinal diseases. ³⁴ Conversely, previous studies have cited tamsulosin in relation to its potential association with retinal detachment, thus providing evidence of possible variations in retinal effects within the alpha-1 antagonist drug class. ²⁵ In addition to selectivity, it is important to highlight that doxazosin and tamsulosin are intrinsically different compounds, as doxazosin is a quinazoline while tamsulosin is not. ³⁵ Pharmacological differences can perhaps explain the decreased adverse ocular symptoms detected by FAERS analysis for doxazosin compared to tamsulosin, but clinical trials are warranted to better understand this relationship.

While predominantly linked to tamsulosin and alpha-1 antagonists, IFIS has also been observed in association with finasteride usage. Prospective studies, complemented by multivariate analysis, have substantiated statistically significant associations between finasteride usage and IFIS, with P-values of 0.014 and 0.015, respectively.^31,36 Debates exist in the medical field concerning the management of finasteride-induced IFIS, likely due to limited studies investigating this association. Some studies have recommended a temporary 2-week withdrawal of treatment before cataract surgery, whereas other studies suggest a reduction in dosage of the BPH medication.^22,37 IFIS has even been found to occur years after discontinuation of alpha-1 antagonists, suggesting the longitudinal nature that IFIS may arise with finasteride intake. ³⁸ The underlying mechanism by which finasteride can induce IFIS remains unknown, and experimental studies are needed to better understand this association.

In addition to IFIS, finasteride has also been seen to be associated with other ocular effects. Finasteride has been shown to downregulate androgen receptors and lead to tear film breakup and disruption in tear flow.^10,39 Further, meibomian gland dysfunction has also been observed in androgen deficiency, a condition believed to be induced by 5-ARIs usage.^40,41 Dysfunction in both the lacrimal and meibomian glands can lead to conditions such as blepharitis, xerophthalmia, and other clinical presentations that may resemble conjunctivitis. ⁴² FAERS analysis reveals positive drug-adverse event signals for finasteride and its potential associations with blepharitis, xerophthalmia, and conjunctivitis, but FAERS cannot definitively confirm the presence of a causation between these events. In their case-control study, Kyun Shin et al. identified ocular abnormalities in patients taking 5-ARIs, such as macular holes and foveal cavitation. ¹¹ Hoai Nguyen et al. corroborate this association through a retrospective chart review by finding significance for finasteride intake and retinal dysfunction. ⁴³ The findings of the FAERS analysis on retinal effects related to finasteride provide substantial justification for additional studies to elucidate the mechanism behind finasteride-induced retinal toxicity.

While our study boasts significant strengths, including the utilization of real-world patient data from the FDA’s national database to assess occurrences, clinical outcomes, and side effects of alpha-1 antagonist and 5-ARIs therapy, it is essential to acknowledge certain limitations in this investigation. The FAERS database primarily relies on voluntary submissions of spontaneous reports, which may lead to underreporting, false reporting, and incomplete coverage of all adverse events. Another consideration is that FAERS does not report laboratory values, patients’ medical history, or other pertinent factors, limiting the assessment of context and severity of reported adverse events. As such, limitations in the FAERS database regarding the availability of detailed patient information can lead to confounding factors such as comorbidities and the concurrent use of multiple drugs, which can obscure observed outcomes in FAERS analysis. To minimize this effect, we employed stringent criteria for disproportionality analysis, aiming to reduce the impact of external variables on our findings. Despite the stringent criteria applied in this disproportionality analysis, it is important to emphasize that this method identifies associations rather than establishing causation between drug exposure and adverse events. Independent experimental studies are necessary to further investigate and validate these associations. Additionally, an inherent limitation of the FAERS database is the lack of information regarding the number of prescriptions for a specific drug, which may potentially lead to an overestimation or underestimation of associated risk. Further, our analysis primarily relied on doxazosin and tamsulosin reports for alpha-1 antagonists, limiting the ability to comprehensively compare the entire alpha-1 blockers drug class due to the limited number of case reports available for alfuzosin and terazosin. Prescription patterns for alpha-1 blockers show that tamsulosin and terazosin comprise at least 70% of all BPH medications, yet terazosin has little statistical significance in FAERS data analysis. ⁴⁴ The absence of prescription data limits the ability to calculate incidence rates of ocular adverse events or adjust for drug exposure duration. Furthermore, given the high volume of tamsulosin reports in the FAERS database, the observed ocular adverse events may primarily reflect underlying prescribing trends. It remains unclear if terazosin provides a better ocular safety profile compared to the other alpha blockers or if it is due to underreporting of adverse events in the database. The limited reporting of less commonly prescribed drugs, such as silodosin and alfuzosin, restricts the feasibility of meaningful comparative analysis. Further investigation into these findings is warranted through clinical studies that control for confounding variables such as age, comorbidities, and concomitant medications to strengthen the validity of this association.

Conclusion

The FAERS disproportionality analysis calls for further investigation to comprehend the causality between alpha-1 antagonists and ocular adverse effects such as IFIS, retinal symptoms, and dacryocystitis, as well as between 5-ARIs and ocular adverse events such as retinal symptoms, xerophthalmia, and other inflammatory processes in the eye. Future studies that control for potential confounders and aim to establish a causal mechanism for these findings are essential.

Ethical Approval Statement and Consent to Participate

Not required as this study is exempt by the Rutgers New Jersey Medical School Institutional Review Board. Requirement for informed consent was waived due to de-identified nature of the data.