Urethral stricture disease is one of the oldest described urologic pathologies
and urethroplasty is associated with high success rates. Many urethral strictures
are thought to arise from iatrogenic injury or radiation therapy which can create
ischemic insults to the urethra. In developed countries, most urethral strictures
are idiopathic; therefore, much is still unknown about the etiology and
pathogenesis of this disease. Testosterone is known to mediate vasculogenesis
through vascular endothelial growth factor (VEGF) and hypoxia inducible
Urethral stricture disease was described as early as the sixth century BC in ancient India and was treated with dilation from a reed catheter at that time . Although it is one of the oldest described pathologies in urology and medicine, the etiology remains poorly understood in a significant number of patients. The most common etiologies for anterior urethral strictures are iatrogenic, infectious, traumatic, and lichen sclerosus (LS) disease (formerly known as balanitis xerotica obliterans). In developed countries, an idiopathic or unknown etiology accounts for 34%–41% of anterior urethral strictures [2, 3, 4, 5]. Some idiopathic strictures may be the result of unrecognized perineal trauma; however, a lot remains poorly understood about the etiology of many strictures. Iatrogenic strictures are typically the result of transurethral instrumentation/catheterization, hypospadias surgery, or prostate cancer treatment. These insults typically result in an ischemic injury to the urethra leading to stricture formation.
Angiogenesis mediates wound healing following an ischemic insult. Multiple
models have demonstrated the role of androgens in the regulation of ischemia
induced angiogenesis [6, 7]. Androgens have been shown to modulate angiogenesis
through vascular endothelial growth factor (VEGF) and hypoxia inducible
Sex hormones have long been considered in the pathogenesis and treatment of urethral disorders, namely hypospadias. Exposure to estrogens has been shown to result in arrested urethral development. Alternatively, testosterone exposure to male mice in utero resulted in a more robust peri-urethral spongiosal tissue . Androgen stimulation prior to hypospadias surgery was first used in 1971 . Preoperative testosterone has several theoretical advantages including increased penile and glanular size as well as an increase in prepucial vascularity [11, 12, 13, 14, 15]. Theoretically, improved tissue quality and vascularity would result in better wound healing and outcomes. Results of hormonal stimulation on hypospadias outcomes are conflicting [16, 17] and the use of preoperative testosterone remains controversial.
As the understanding of the role of testosterone in urethral development and angiogenesis has grown, it has spurred an interest beyond hypospadias and into other urethral pathologies including urethral stricture disease. The objectives of this review are to discuss the roles of (1) testosterone in urethral vascularity, (2) TD and urethral stricture disease, (3) testosterone supplementation on urethral vascularity, and (4) future directions of testosterone and stricture disease.
Over the last several years there has been a growing interest in testosterone
and adult urethral pathologies. The first series that spurred this interest
evaluated testosterone and urethral erosion following artificial urinary
sphincter (AUS) placement . The authors had noticed an increase in AUS
erosions in men with TD. In this paper, Hofer et al.  evaluated serum
testosterone levels in 53 consecutive patients who presented for follow-up after
AUS placement. They defined TD as
Prior pelvic radiation therapy, AUS surgery, and prior urethral reconstruction are known risk factors for AUS urethral erosion [20, 21, 22] and all impact periurethral vascularity. Radiation therapy creates an obliterative endarteritis, and prior urethral dissection places the urethra at risk of partial devascularization and atrophy . Compromise to urethral vascularity appears to confer the risk of urethral sub-cuff atrophy and erosion. Since testosterone is known to mediate angiogenesis, this work stimulated further investigations regarding testosterone’s impact on urethral vascularity .
Following the findings by Hofer et al.  in 2016, the same group
explored androgen mediated vascularity in men with normal and low serum
testosterone levels. They compared androgen receptor (AR) expression, its
downstream target the angiopoietin-1 receptor (TIE-2), and the overall
vascularity or vessel count in urethral stricture tissue of men who underwent
urethroplasty. The cohort consisted of 11 men who had a serum testosterone level
within 2 years of urethroplasty. They found decreased expression of AR (1.11%
high power field [HPF] vs 1.62, p = 0.016), TIE-2 (1.84% HPF vs 3.08,
p = 0.006), and overall vessel count (44.47 vessels/HPF vs 98.33,
p = 0.004) in men with serum testosterone less than 280 ng/dL. They also
noted a non-significant correlation between vessel count and serum testosterone
. This study consisted of a very select cohort of patients. During the study
period, approximately 1200 patients underwent urethroplasty at this institution,
but only 11 met inclusion criteria of having perioperative serum testosterone
level which certainly introduces a degree of selection bias. Despite the
limitations of this article, the authors suggest a mechanistic model of low serum
testosterone on decreased urethral and corpus spongiosum vasculogenesis regulated
through the AR and TIE-2 receptors . AR mediated vasculogenesis is complex
and there are likely additional factors involved in this process within the
urethral and periurethral tissue such as VEGF or HIF-1
Levy et al.  explored pathological markers in urethral stricture tissue of LS and non-LS patients. The authors’ objective was to evaluate the pathophysiology of LS strictures by analyzing protein expression related to inflammation, cell cycle disruption, oxidative stress, hormone receptor status, and infection. Admittedly, the goal of this paper was not to explore androgen specific effects on urethral strictures. They examined tissue from 81 urethral strictures and found loss of AR in 43% of all strictures. There was no difference between LS and non-LS strictures. Interestingly, they also found that nearly two-thirds of strictures expressed high levels of VEGF . This series did not assess the serum testosterone levels and therefore conclusions regarding the impact of serum testosterone on AR and VEGF cannot be drawn from this series. However, the results are interesting and add to the work by Hofer et al.  demonstrating alterations in the expression of the AR in urethral stricture disease.
Spencer et al.  performed a retrospective review of patients
undergoing urethroplasty by two surgeons at two institutions. Preoperative
testosterone assessment was part of the standard practice of both surgeons. They
excluded patients with a history of pelvic radiation, prostatectomy, or pelvic
fracture urethral injury. Overall 157/202 met inclusion criteria of which 115 had
preoperative testosterone. These authors found 56.5% of men undergoing
urethroplasty had TD as defined by serum testosterone
The authors then analyzed stricture characteristics among men with low and
normal testosterone levels. Men with low testosterone levels had higher BMI, 36
Bonilla et al.  recently published an abstract form a cross
sectional case-control study of men presenting to one institution evaluating TD
in men with urethral stricture disease. They compared serum testosterone levels
in men presenting for urethral stricture evaluation to men presenting for
non-voiding related complaints. They had 120 men with urethral stricture and 41
controls. There were no differences in demographics or comorbidities between
groups. Mean serum testosterone levels were significantly lower (391 ng/dL vs 495
As the evidence supporting a link between low serum testosterone and urethral vascularity grows, efforts shifted toward determining if urethral vascularity could be improved with hormone supplementation. Yura and colleagues  first evaluated this in a rat model. They divided 24 Sprague Dawley rats into four groups: non-castrate control, castrate, castrate with testosterone supplementation, and castrate with estrogen supplementation. They compared AR, TIE-2, and CD31 expression between groups. CD31 is a sensitive marker for vascular tissue. CD31 was decreased in castrated rats compared to controls. AR and TIE-2 were not detected in the castrate group. Following supplementation with testosterone the overall vessel count, AR, and TIE-2 expression increased significantly. Testosterone restored CD31 and AR expression to higher levels than the non-castrate control group . Estrogen supplementation improved CD31 but not AR or TIE-2 expression . These findings demonstrate that testosterone supplementation restores periurethral vascularity in an animal model.
The same group then assessed the impact of hormone supplementation on urethral
tissue following urethroplasty in a rat model . They allocated 48 rats to the
same groups (non-castrate control, castrate, castrate with testosterone
supplementation, and castrate with estrogen supplementation). In each group half
of the rats underwent a Heineke Mikulicz style urethroplasty. CD31 expression was
used to assess tissue vascularity and it was increased post-operatively in the
control group as well as the testosterone and estrogen arms compared to the
castrate arm. AR expression was slightly decreased in those that received surgery
compared to no surgery in the testosterone supplementation arm (5.21% vs 4.24%,
p = 0.042). TIE-2 expression was increased in both the control (0.43%
vs 0.85%, p = 0.001) and testosterone supplementation cohort (0.20% vs
The fascinating work by this group demonstrates that not only does testosterone supplementation improve urethral vascularity but that it is also true in a perioperative environment. They also suggest that postoperative angiogenesis is an androgen driven process. The rats who underwent surgery did not have urethral stricture disease and it remains unclear how urethral pathology would impact these results. Prior work has shown urethral stricture tissue has decreased vascularity ; therefore, it is reasonable to believe postoperative angiogenesis would still be improved with androgen supplementation. Additionally, the comparison group was not just TD, but castrate and it is possible that these results may not extrapolate to subjects with less degree of TD.
Over the last 5–6 years, much has been learned regarding the impact of testosterone on urethral vascularity and stricture disease (Table 1, Ref [18, 19, 23, 24, 25, 26, 27, 28]). However, there is still more work to be done as this emerging area translates into clinical practice. First, the role of testosterone on urethral stricture etiology remains unclear. Is there a direct pathogenesis where low serum testosterone creates an ischemic environment leading to urethral strictures in men? If so, what portion of idiopathic urethral strictures are secondary to TD? Does TD and poor urethral vascularity prevent wound healing following an insult from iatrogenic or straddle trauma? If this is true, then is testosterone supplementation protective against urethral stricture disease?
|Study (year)||Subjects (n)||Design||Main finding||Additional findings|
|Hofer et al. ||Human (53)||Retrospective cohort study||AUS erosion independently associated with TD*||90% of men with AUS erosion had TD*|
|Wolfe et al. ||Human (161)||Retrospective cohort study||TD* associated with AUS erosion on multivariate analysis||OR = 2.519 for AUS erosion with TD*|
|Hofer et al. ||Human (11)||Retrospective cohort study||Urethral stricture tissue in TD* men had less AR expression||TIE-2 and vessel count also decreased in men with TD*|
|Levy et al. ||Human (81)||Retrospective cohort study||AR loss in 43% of all strictures||VEGF upregulated in 66% of strictures.|
|Spencer et al. ||Human (115)||Retrospective review from 2 centers||TD present in 56.5% of men with urethral stricture||Strictures were significantly longer in men with TD|
|Bonilla et al. ||Human (161)||Case control, cross-sectional analysis||TD was more common in men with urethral stricture (35.8 vs 14.5%, p
||FSH (10.7 vs 5.01 mIU/mL, p |
|Yura et al. ||Sprague-Dawley Rats (24)||Multi-arm study||Testosterone supplementation improved AR and CD31 expression compared to castrate rats||Estrogen supplementation only improved CD31|
|Yura Gerbie et al. ||Sprague-Dawley Rats (48)||Multi-arm study||AR and TIE-2 increased in testosterone supplementation group following urethroplasty||AR and TIE-2 correlated with postoperative vascularity suggesting mechanistic relationship|
|*TD defined by serum testosterone |
Second, it is important to understand if TD impacts surgical outcomes. It is plausible that urethral stricture recurrence following surgery could be reduced by improving urethral vascularity and subsequently wound healing. Further, sexual side effects following urethroplasty have gained significant attention in the literature and are thought to be the result of vascular insults during surgery. The role of transecting vs non-transecting anastomotic urethroplasty is a highly debated topic in reconstructive urology. This debate focuses on the benefits of preserving the antegrade blood supply to the corpus spongiosum. A recent randomized controlled trial comparing excision and primary anastomosis (EPA) and buccal mucosa graft urethroplasty found a higher rate of reduced glans filling in the EPA group . As we learn more about the impact of testosterone on urethroplasty outcomes, it will be interesting to see if testosterone not only changes outcomes but also approaches to urethral reconstruction.
Vascularity within the urethra and corpus spongiosum is mediated through androgen pathways. Further, it appears a large number of men with urethral stricture disease have TD. Supplementation with testosterone appears to improve urethral vascularity within animal models. As this area of study continues to emerge, we will hopefully learn more about urethral stricture etiologies and the impact of testosterone on surgical outcomes.
MAMH, FAY, DWB all contributed to design, data analysis, writing, and reviewing of the manuscript. All authors reviewed and approved the final manuscript.
This research received no external funding.
MAMH—no conflicts of interest; FAY—on the advisory board and is a consultant for Coloplast, a speaker for Antares Pharma, a speaker for Clarus Therapeutics, on the advisory board for Promescent, and a research investigator for Viome; DWB—no conflicts of interest. FAY is serving as one of the Guest editors of this journal. We declare that FAY had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to TA.
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