Low free testosterone and anterior urethral stricture disease: a coherent signal still in search of a causal test

Introduction

Anterior urethral stricture disease (aUSD) remains one of the few common urological conditions for which the majority of charts still read “idiopathic”. Depending on the series, between 40% and 60% of anterior strictures have no identifiable cause, and the cohort reported here is no exception, with 84 of 154 men (55%) classified as idiopathic (1,2). That label is not merely an epidemiological curiosity. It is the reason our armamentarium remains almost entirely mechanical: we dilate, incise, excise and substitute, but we have no medical therapy that modifies the disease process, and no satisfying answer for the 40-year-old man who asks why his bulbar urethra scarred when his neighbour’s did not. Any candidate mechanism that is measurable in serum, biologically plausible and potentially modifiable therefore deserves careful attention.

In this issue of Translational Andrology and Urology, Lozano and colleagues report a secondary analysis of the multicentre, National Institute of Diabetes and Digestive and Kidney Diseases-funded cohort originally assembled to phenotype the inflammatory biology of aUSD (1,3). Their question is disarmingly simple: do circulating sex hormones differ between men with anterior strictures and men without, and do they track disease severity? The answer they obtain is narrow but interesting, and it deserves both credit and scrutiny.

What the study adds

Serum from 154 men undergoing anterior urethroplasty and 9 men undergoing vasectomy was assayed by enzyme-linked immunosorbent assay (ELISA) for total testosterone (TT), free testosterone (fT), estradiol, progesterone and cortisol. Of these five analytes, only fT distinguished the groups: median 1.08 vs. 2.13 pg/dL (P=0.046). In univariable logistic regression the odds of stricture fell as fT rose [odds ratio (OR) 0.29, 95% confidence interval (CI): 0.13–0.60], and the association survived adjustment for age, body mass index (BMI) and diabetes [adjusted OR 0.33, 95% CI: 0.13–0.81]. Within the stricture cohort, fT declined monotonically across the Length, Segment, Etiology (LSE) length strata: 1.20 pg/dL for L1 (≤2 cm), 1.05 for L2 (>2–7 cm) and 0.868 for L3 (>7 cm) (P=0.01), with post-hoc differences of −0.29 for L2 vs. L1 and −0.39 for L3 vs. L1. Neither TT nor any other hormone differed between cohorts, between stricture aetiologies, or—after adjustment—with histological inflammation (1).

Three features make this more than another positive association study. First, the cohort is prospective, multicentre and unusually well characterised: strictures were staged with a validated system and graded histologically for inflammation by two pathologists (3,4). Second, the length gradient constitutes a dose-response relationship, which is one of the more persuasive of the Bradford Hill considerations and is difficult to generate by chance alone. Third, and most importantly, the finding does not stand alone. Puche-Sanz et al. found lower TT in 149 men with strictures than in 67 controls, with directionally consistent though non-significant effects for fT and bioavailable testosterone (5); Spencer et al. reported clinically low TT in 57% of men with aUSD versus 28% of age-matched controls, again associated with longer strictures (6); Mondal et al. linked low TT to stricture length and post-urethroplasty recurrence (7); and Özsoy et al. found lower total and bioavailable testosterone in men who recurred after internal urethrotomy (8). A TriNetX analysis of 12,556 eugonadal and 488 hypogonadal men undergoing urethroplasty found a higher 5-year redo rate in the hypogonadal group (11% vs. 6%) (9). The artificial urinary sphincter (AUS) literature points the same way, with low testosterone present in 71–90% of men sustaining cuff erosion (10,11). Five study designs, five countries, one direction of effect.

Why the biology is plausible

Epidemiological consistency would mean less without a mechanism, and here the mechanism is more than hand-waving. Androgen signalling is indispensable for urethral plate tubularisation in utero, and the adult corpus spongiosum retains androgen receptor (AR) expression. Hofer et al. showed that stricture specimens from hypogonadal men have reduced AR and angiopoietin-1 receptor expression and lower periurethral vessel density than specimens from eugonadal men (12). Crucially, this appears reversible: in a hypogonadal rodent model, testosterone repletion restored periurethral vascularity (13), and in a castrated rabbit model of bulbar end-to-end anastomosis, perioperative testosterone propionate increased luminal diameter, enhanced periurethral vascularisation and suppressed fibrosis-related gene expression one month after surgery (14).

Lozano et al. assemble these strands into a “two-hit” hypothesis: an otherwise subclinical urethral insult—an endoscopic instrument, a straddle event, a catheter—meets a spongiosum whose capacity to regenerate is compromised by androgen deficiency, and the tissue heals by fibrosis rather than by repair (1). This is an attractive framework precisely because it explains the idiopathic category without requiring a hidden aetiology: the insult may have been trivial and forgotten, and it is the host response, not the insult, that determines whether a stricture forms. It also aligns with the group’s own earlier observation of unexpectedly high rates of chronic inflammation within idiopathic stricture tissue (3), and with emerging evidence for heritable susceptibility to stricture formation (15).

A parallel from paediatric practice is instructive, and it cuts both ways. Preoperative androgen stimulation before hypospadias repair rests on the same vascular premise, and the histological evidence for it is direct: in a randomised study, topical testosterone propionate increased both the number and the volume density of blood vessels within the prepuce (16). Yet androgens simultaneously retard re-epithelialisation, with 5α-dihydrotestosterone delaying wound closure and AR signalling sustaining a pro-inflammatory phenotype that impairs healing (17,18). Paediatric practice has responded by separating the two effects in time, withdrawing androgen approximately one month before repair (19). The analogy should not be pressed too far—the infant genital tubercle is developmentally competent, AR-rich mesenchyme, whereas adult spongiofibrosis is scar in which AR expression is itself reduced (12)—but the vascular arm is common to both.

Reading the numbers carefully

That said, the interpretive load this dataset is being asked to carry exceeds what it can comfortably bear, and the authors are commendably frank about several of the reasons.

The control group is the most obvious constraint. Nine men is not a comparator group so much as a reference point, and the 17:1 imbalance means that the case–control estimates rest almost entirely on nine observations. The instability is visible in the model itself: the intercept of the adjusted regression carries a 95% CI of 0.04 to 411, a signature of near-separation. Controls were also 15 years younger (median 32 vs. 47.5 years) and were men presenting for vasectomy—that is, men who are by definition fertile, partnered and healthy enough to be planning family completion. Statistical adjustment for age cannot fully repair a comparison between populations that differ so systematically.

The assay deserves equal attention. Direct immunoassay measurement of fT is widely regarded as unreliable; equilibrium dialysis with mass spectrometry is the reference method, and calculated fT derived from TT, sex hormone-binding globulin (SHBG) and albumin using the Vermeulen equation is the accepted clinical surrogate (20,21). The kit used here has a stated range of 0.1–60 pg/mL against a clinical reference interval of roughly 35–155 pg/mL, and the values it returned are far below what a clinician would recognise. The authors correctly caution against cross-study comparison, but the consequence runs deeper: the headline effect size, “a 1-unit increase in fT is associated with a 67% reduction in the adjusted odds of stricture”, is expressed in units that cannot be mapped onto a threshold, a target or a dose. It tells us that a gradient exists; it cannot tell us where along that gradient a man becomes at risk.

SHBG is the missing variable that would tie the analysis together. fT differed while TT did not, and the arithmetic difference between the two is almost entirely binding-protein biology. SHBG rises with age and falls with obesity and insulin resistance, so an fT signal without an SHBG measurement is ambiguous between gonadal output and metabolic phenotype. This matters concretely: men with L3 strictures were older (median 54 vs. 38.5 years), more comorbid and considerably more obese (BMI 36.5 vs. 28.9 kg/m²) than men with L1 strictures, yet the length analysis was an unadjusted one-way ANOVA. The fT-length gradient—arguably the study’s most interesting finding—is therefore the one least protected against confounding.

Three further caveats warrant mention. Reverse causality cannot be excluded in a cross-sectional design: men with panurethral disease have often endured years of obstruction, recurrent infection and impaired sexual function, all of which suppress the hypothalamic-pituitary-gonadal axis. Low fT may be a consequence of longstanding stricture disease as easily as a cause of it. Missing data ranged from 8% to 10% per analyte overall but reached 30% in the non-inflamed subgroup versus 5% in the inflamed subgroup; with listwise deletion, differential missingness of that magnitude could plausibly generate the transient TT signal that then disappeared on adjustment. Finally, five hormones were tested across six pre-specified questions without correction for multiplicity, and several of the surviving P values (0.046, 0.038, 0.042) sit close enough to the threshold that they should be treated as hypothesis-generating rather than confirmatory. None of this invalidates the work. It does mean that the appropriate reading is “consistent with a growing literature” rather than “demonstrates”.

From association to the bedside

The authors suggest that testosterone should be checked, and replaced if low, before procedures requiring urethral instrumentation. This is where an editorial should be most careful, because the gap between a plausible association and a justified intervention is exactly where urology has previously gone wrong.

Measuring is defensible; treating is not yet. A morning TT with SHBG is inexpensive, low-risk, and in a population with a median BMI above 30 there are independent reasons to know the answer. If we measure, however, we should measure properly: two fasting morning samples, TT by mass spectrometry where available, SHBG and calculated fT, with luteinising hormone to localise the lesion. The 2025 European Association of Urology guidance retains a TT threshold of ≤12 nmol/L in symptomatic men and explicitly recommends calculated fT where SHBG is likely to be perturbed—which describes most obese men with long strictures (22,23). A single non-standardised ELISA drawn on the morning of surgery, in a man who is fasted, anxious and about to be anaesthetised, is not a diagnosis of hypogonadism.

Treating is a different proposition, and the honest position is that no human data show that correcting testosterone improves any urethral outcome. Indeed, within the same TriNetX cohort, hypogonadal men already established on testosterone replacement at the time of urethroplasty had a higher 5-year redo rate than their replacement-naïve hypogonadal counterparts (15% vs. 7%; relative risk 1.8, 95% CI: 1.1–3.3, P=0.02) (9). That almost certainly reflects confounding by indication in a retrospective database rather than genuine harm, but it is a sobering observation, and it undercuts any assumption that normalising a serum androgen value will of itself improve urethral outcomes. Two considerations should temper enthusiasm. First, safety: TRAVERSE established non-inferiority for major adverse cardiovascular events over a mean 22 months, but with excess atrial fibrillation, acute kidney injury and pulmonary embolism in the testosterone arm (24). Second, and more pertinent to this population, exogenous testosterone suppresses spermatogenesis. The idiopathic strictures in this cohort had a median age of 41 years, and L1 strictures a median of 38.5; a substantial proportion of the men we would be treating are of reproductive age, and fertility loss is a poor trade for an unproven surgical benefit. If androgen support is to be explored in this group, fertility-sparing strategies deserve consideration alongside conventional replacement.

There is also a question of framing that the preclinical data help answer. A four-to-eight-week preoperative course intended to optimise periurethral vascularity before urethroplasty is a fundamentally different intervention—in duration, risk and regulatory status—from initiating lifelong replacement in a man in his fourth decade. The rabbit data speak to the former, not the latter (14). Pending evidence, a pragmatic position might be to maintain a low threshold for hormonal assessment in men with long or panurethral idiopathic disease, in those recurring after technically sound urethroplasty, and in candidates for AUS placement, where the erosion literature is strongest (10,11)—while reserving replacement for men who meet independent diagnostic criteria for symptomatic hypogonadism, treated for that indication rather than for their urethra.

A research agenda

The field now has enough consistent observational data that further case–control series will add little. Four steps would move it forward.

The first is a properly powered prospective cohort with a standardised endocrine protocol: two fasting morning samples, TT by liquid chromatography-tandem mass spectrometry, SHBG, calculated or dialysis-derived fT, and gonadotrophins, compared against a eugonadal control group matched on age and BMI rather than convenience-sampled. The consistency of the existing signal justifies that investment.

The second is to exploit the tissue. This group already banks urethroplasty specimens and grades them histologically; correlating serum androgen status with AR expression, vessel density and the extent of spongiofibrosis in the same men would test the proposed mechanism directly rather than inferring it. A serum-only analysis will always be one step removed from the pathology.

The third is to address confounding and reverse causality by design. Mendelian randomisation using published genome-wide association data for testosterone and SHBG against stricture phenotypes is comparatively inexpensive and would help distinguish causation from the metabolic confounding that a cross-sectional design cannot exclude—an approach that complements the emerging genomic work on stricture susceptibility (15).

The fourth is an interventional trial, which is ultimately the only test that matters. A definitive trial powered on redo urethroplasty at five years would be prohibitively large given event rates of 6–11% (9). A more tractable design would be a phase II randomised trial of perioperative androgen supplementation versus placebo in hypogonadal men undergoing anterior urethroplasty, with surrogate endpoints drawn directly from the rabbit model—periurethral vascularity, fibrotic gene expression and healing on the excised specimen—alongside 12-month anatomical patency and patient-reported outcomes. The paediatric experience argues for a specific schedule—a defined preoperative course followed by withdrawal before incision rather than continuous perioperative exposure—and for buccal mucosa graft onlay as the natural setting, since graft take depends directly on recipient bed vascularity. The reconstructive networks that generated the present cohort are well placed to deliver exactly this.

Conclusions

Lozano and colleagues have produced a careful, transparently limited analysis that adds a further consistent observation to a literature now spanning five independent designs: men with anterior urethral strictures have lower bioavailable testosterone than men without, and lower levels track with longer disease. The small control group, the non-standard assay, the absence of SHBG and the cross-sectional architecture mean the study cannot establish causation, and the authors do not claim that it does. What it does accomplish is to make the impaired-healing hypothesis harder to dismiss and to sharpen the question that the field must now answer. The androgen–urethra axis has moved beyond the point where further association studies are informative. It deserves a trial.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0741/coif). L.K. serves as a consultant & proctor for Boston Scientific, Coloplast and Medtronic, and received financial compensation for lectures & presentations by Boston Scientific, and cost compensation for attending scientific meetings organized by the companies Boston Scientific, Coloplast and Medtronic. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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