|Year : 2023 | Volume
| Issue : 2 | Page : 126-132
Effect of preoperative estrogen on complications after proximal hypospadias repair: A randomized controlled trial
Akash Bihari Pati1, Pritinanada Mishra2, Santosh K Mahalik1, Bikasha Bihary Tripathy1, Manoj Kumar Mohanty1
1 Department of Pediatric Surgery, AIIMS, Bhubaneswar, Odisha, India
2 Department of Pathology, AIIMS, Bhubaneswar, Odisha, India
|Date of Submission||04-Nov-2022|
|Date of Decision||20-Feb-2023|
|Date of Acceptance||09-Mar-2023|
|Date of Web Publication||31-Mar-2023|
Akash Bihari Pati
Department of Pediatric Surgery, AIIMS, Bhubaneswar, Odisha
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: Proximal hypospadias repair has many postoperative complications such as urethrocutaneous fistulae, wound dehiscence, and urethral stricture. The beneficial effect of estrogen to promote wound healing has been known. We designed a study to determine whether preoperative stimulation of tissue with estrogen can reduce the postoperative complications associated with wound healing in patients undergoing hypospadias repair.
Methods: Patients with proximal hypospadias requiring two-stage repairs (chordee correction followed by urethral tubularization) were randomized to estrogen and control groups before the second stage of surgery. In the former, topical estrogen cream (0.5 mg of estriol) was applied to the ventral penis for a month, whereas normal saline gel was applied to the latter; the urethroplasty was carried out thereafter. Patients were followed up for complications.
Results: There were 29 patients in the estrogen group and 31 in the placebo group after the exclusion criteria were met. There was no significant difference in the overall postoperative complications between the estrogen group (44.8%) and the placebo group (51.6%). The occurrence of urethrocutaneous fistula (37.9% vs. 51.6%) and dehiscence (41.4% vs. 45.2%) was not significantly different between the estrogen and placebo groups. Neourethral stricture occurred in four patients in the estrogen group, while none of the patients in the placebo group developed stricture.
Conclusions: The preoperative application of topical estrogen cream to the ventral penis failed to demonstrate any significant effect on wound healing and complications.
|How to cite this article:|
Pati AB, Mishra P, Mahalik SK, Tripathy BB, Mohanty MK. Effect of preoperative estrogen on complications after proximal hypospadias repair: A randomized controlled trial. Indian J Urol 2023;39:126-32
|How to cite this URL:|
Pati AB, Mishra P, Mahalik SK, Tripathy BB, Mohanty MK. Effect of preoperative estrogen on complications after proximal hypospadias repair: A randomized controlled trial. Indian J Urol [serial online] 2023 [cited 2023 May 31];39:126-32. Available from: https://www.indianjurol.com/text.asp?2023/39/2/126/373131
| Introduction|| |
Hypospadias is one of the most common birth defects. The anomaly is a spectrum, from a megameatus requiring no treatment or a cosmetic repair to the perineal hypospadias with chordee mandating a staged genital reconstruction. All repairs aim to achieve a near-normal genital appearance and function, and the various techniques in vogue testify to the complexity of the problem. The repair of hypospadias is challenging, even for a seasoned pediatric urologist.
The repair of proximal hypospadias with severe chordee often includes a urethral plate division for satisfactory orthoplasty. The surgeon can choose a single-stage or staged repair; the latter has been associated with fewer complications. The two-staged repair, consisting of chordee correction-mobilizing the skin to the ventral area of the penis followed by a urethroplasty 6 months later, has a complication rate ranging from 23.5% to 70%. Multiple logistic regression analysis has demonstrated a higher fistula rate with a more proximal meatus and reoperation. Numerous modifications in surgical procedures are largely technical nuances to limit complications and failure rates. Recently, few studies have explored the relationship of tissue healing with postoperative complications in hypospadias repair.,
Tissue injury is followed by a complex, orchestrated healing process influenced by sex steroids-estrogen and testosterone. The effect of estrogen on wound healing has been investigated in animal models and humans since 1953. Estrogen deficiency leads to cutaneous aging and delays wound repair in postmenopausal women. Dermatologists use estrogen cream to accelerate collagen deposition and decrease wrinkles in old age. Similarly, preoperative administration of testosterone can increase tissue vascularity and penile size in hypospadias but has an equivocal role in the genesis of postoperative complications.,
We hypothesized that the preoperative application of estrogen would enhance urethroplasty healing, thereby reducing complications. We aimed to study the effect of the preoperative application of estrogen cream to the skin of the ventral penis (preputial flap) on the occurrence of postoperative complications after staged proximal hypospadias repair.
| Methods|| |
A prospective randomized controlled trial was designed for patients of hypospadias presenting to a tertiary teaching public hospital and those requiring multi-staged procedures for management. The study was initiated after obtaining approval from the Institutional Scientific Evaluation Committee and Ethics Committee (IM-F/17-18/47) and was registered with the National Clinical Trial Registry (2018/01/011474). Parents and caregivers of patients participating in the study were explained about the procedure in detail, and a participation leaflet was shared with them, elaborating on frequently asked queries. Written informed consent was obtained from parents and caregivers, and assent to participate in the study was obtained from patients above 7 years of age.
We resort to a staged repair for hypospadias in patients where it is necessary to transect or excise the urethral plate during the repair. During the first stage, the penis is straightened, and the urethral plate is substituted with a flap/graft of either preputial or extragenital origin. The second stage is carried out 6 months later when the graft is tubularized. Patients who had undergone the first stage of repair with a Byar's preputial flap and reported for the second stage during 2018–2020 were included in the study. The exclusion criteria were: very short penis (stretched penile length [SPL] <20 mm), disorders of sex differentiation, syndromic associations, patients who had received local or parenteral testosterone therapy, and re-operative hypospadias. All patients were examined at 6 months following the first stage of surgery. Patients who failed graft take-up after the first stage of surgery requiring revisional first-stage surgery were excluded. Patients with supple unscarred skin at the ventral surface of the penis (after the first stage) were randomized to two groups: the estrogen group and the control group [Figure 1]. Randomization was done by a nursing officer based on the random numbers assigned by a computer-generated block of four. The nursing officer was responsible for allotting a study number to the participant and providing the estrogen cream and placebo cream, as well as necessary advice to the patient regarding the application of the cream. After applying the creams for 1 month, the tubes were to be returned to the nursing officer on the day before surgery to ensure that the cream had been used by the patient. The surgeons were blinded regarding the group to which the patient belongs.
Patients in the estrogen group were advised to apply estrogen cream (1 mg of Estriol and 0.1 mg of chlorhexidine hydrochloride as a preservative in 1 g of cream) on the ventral skin of the penis, destined to be tubularized during urethroplasty. An applicator that delivered 0.5 g of the cream to the penile skin [Figure 2] was used to apply the cream. Parents massaged the cream on the flap skin on the ventral penis (destined to form the neourethra) for 5 min daily at bedtime, and urethroplasty was performed after 1 month. The patients in the control group underwent urethroplasty after applying the placebo cream in the form of a normal saline gel.
|Figure 2: Applicator used to deliver 0.5 mg of estrogen cream onto the ventral penile skin|
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General anesthesia with a caudal block was used for urethroplasty in all patients. An intravenous antibiotic was administered at induction and continued orally postoperatively till the removal of the stent. Pediatric surgeons of comparable training and more than 5 years of experience carried out surgical procedures. They were blinded regarding the group to which the patient belonged. Measurements of the SPL, corporal body girth at the base of the penis, meatus to glans tip distance (length of urethroplasty), and maximum glans diameter were noted in millimeters (mm) using digital vernier calipers. A strip of skin used as neourethra on the ventral aspect of the penis was marked with a width of 12 mm centering midline. Urethroplasty was performed with a running subcuticular 6–0 absorbable polydioxanone suture over a silicone stent after mobilizing the lateral edges of the skin strip, and care was taken to preserve vascularity. The tunica vaginalis testis (TVT) flap and dartos layers provided additional layers for closure over the neourethra. Postoperatively, patients were continued on continuous bladder drainage, antibiotics, oxybutynin, and laxatives. The primary dressing was changed on postoperative day 5 and reapplied for another 2–3 days in those with residual tissue edema. The urethral stent was removed between the 10 and 14 postoperative days. The patients were followed up for a period of 2 years following surgery.
During the second stage of urethroplasty, a skin biopsy (approximately 0.5 mm × 0.5 mm) was harvested from the area of the cream application. The pathologist was blinded regarding the group from which the tissue was collected for histopathology. Immunohistochemical examination was carried out using monoclonal mouse antihuman CD 31 antibodies on the paraffin-embedded samples of the harvested skin. Areas of high vascularity were identified under low-power fields (×100). Microvessels were identified as capillaries, venules, or arterioles having a single endothelial layer [Figure 3]. Vascularity was counted in three fields within these high vascularity areas seen under low power. The average of three fields was recorded as mean vascular density (MVD) and used for analysis.
|Figure 3: Photomicrograph showing microvessels in skin biopsy. (×100) CD31 highlights the blood vessels (arrows) lined with a single layer of endothelium|
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The investigators examined all patients during the entire study period for adverse effects of estrogen (skin pigmentation and gynecomastia), and an endocrinology consult was obtained. Final postoperative outcomes (fistula, glans dehiscence, urethral stricture, etc.) were noted during the follow-up period of the second stage of surgery. Whenever a urethrocutaneous fistula was identified during the follow-up, the severity of the fistula was measured. The maximum diameter of the fistula was measured using the digital vernier calipers in millimeters (under sedation if required). The severity of the fistula was expressed as a proportion using the formula-Diameter of fistula/length of urethroplasty × 100. The severity of the fistula was calculated as the proportion of the urethroplasty suture line which dehisced or opened. When there were multiple fistulae, the maximum dimensions of the individual fistula were added to measure the severity. In patients developing both glans and urethral dehiscence in continuity, the length of the urethral dehiscence was considered the fistula's diameter. Postoperative obstructive voiding symptoms were managed with dilatation/urethroscopy and redo surgery as appropriate.
Patient's data were collated and analyzed using appropriate nonparametric statistical tests using SPSS 23.0 software (IBM, NY, USA) [Table 1], and a P < 0.05 was considered statistically significant.
|Table 1: Comparison between the control group and estrogen group concerning demographic characteristics and results|
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| Results|| |
We recruited 32 patients in each estrogen and control group after randomization. One patient developed generalized eruptions after the initial application of the cream. We discontinued the application after unblinding and excluded the patient from the study. He made an uneventful recovery from eruptions. Three patients were lost to follow-up and were excluded from the study. Patients in both groups were comparable for age, size of the penis (glans diameter, SPL, and corporal body girth at the base of the penis), and mean length of urethroplasty [Table 1]. Overall postoperative complications were not significantly different in the estrogen group (44.8%) compared to the control group (51.6%).
Urethrocutaneous fistula occurred in 51.6% of the patients in the control group compared to 37.9% in the study population. The severity of the fistula was 8.9% in the study population compared to 18.9% in the control group [Table 1]. A Chi-squared test was used to explore the association between the groups and fistula occurrence. There was no significant difference between the two groups regarding fistula occurrence and severity. The relative risk of developing a fistula with the estrogen application group was 0.75 (95% confidence interval = 0.42–1.27). Given the small number of patients, we performed an “intent-to-treat” analysis with the “last observation carried forward” of our results. The result was insignificant for overall complications, fistula rate, and severity.
The glans dehisced in 12 patients with estrogen application compared to the control group [Table 1]. The patients were further stratified into two groups depending upon a preoperative glans diameter >14/≤14 mm. The relative risk of developing glans dehiscence with a preoperative glans diameter of <14 mm was 1.3 (95% Confidence interval = 0.46–3.8) in the control group, while that for the estrogen group was 0.8 (95% Confidence interval = 0.4–1.6).
Four patients developed urethral stricture during follow-up in the estrogen group. One patient developed a stricture with a diverticulum just proximal to the stricture and underwent redo surgery. Three patients had strictures that were managed with repeated dilatations.
Skin biopsy was done for 25 patients. There was no significant difference in MVD between the two groups [Table 1].
| Discussion|| |
We found that estrogen cream applied preoperatively to penile skin (destined to form the neourethra) failed to significantly reduce postoperative complications such as urethrocutaneous fistula and glans dehiscence. The patients in the study had uniform disease severity, as all had a poor urethral plate with severe chordee requiring transection of the urethral plate. We included only those patients who had undergone Byar's procedure to have uniformity in managing the condition. This is the only study where a comparison has been made between two groups having similar severity and management of the condition.
Despite the availability of adequate care for treating proximal hypospadias, the risk of complications remains high. This has piqued the interest of the hypospadiologist in complementary methods that can be employed to reduce the rate of complications. To achieve more favorable outcomes during the surgical repair of proximal hypospadias by increasing the penile biometry and tissue vascularity, preoperative hormonal therapy has been investigated as a potential treatment modality. The length of the urethral defect, the method of urethroplasty, the level of the surgeon's experience, are important factors. Both estrogen and testosterone have been administered as preoperative hormonal therapy for patients suffering from hypospadias. Estrogen is known to have a beneficial effect on tissue healing, in contrast to testosterone, which is known to promote vascularity but is also reported to have a deleterious effect on the healing of tissues. Although not reported in pediatric patients, there is a risk that systemic exposure to estrogen can lead to the development of breast tissue and a higher risk of breast cancer. We decided to use estrogen as a topical application since it has a negligible systematic effect but a significant effect on the surrounding area. In the research conducted by Paiva et al., the investigators used a topical form of estrogen 1 month before surgery to evaluate any possible effects of this hormone. In light of this, we also chose to administer estrogen before the operation for 1 month.
Proximal hypospadias repair is associated with complications such as urethrocutaneous fistulas and dehiscences up to 70%. It has spurred surgeons to try various techniques to overcome these. Several factors, such as age at repair, meatal locations, suture materials, suturing techniques, and penile biometry have been correlated with the frequency and nature of the complications. Studies relating complication rates to surgeon factors have failed to show a definitive learning curve in the first 50 cases or surgeon experience as an independent risk factor in ensuing complications of hypospadias repair. Studies on postoperative complications and tissue response to sex steroids, androgens, or estrogens are limited. A recent experimental study reported that the speed of repair of subcutaneous tissue is lower in androgen-inhibited hypospadias rats. Similarly, prospective randomized studies demonstrated androgens to increase penile length and glans size in hypospadias patients., Indeed, hypospadiologists employed preoperative administration of androgens (parenteral/local) to increase the tissue bulk of the penis expecting ease in technique and lowering complications. However, such therapy has failed to decrease urethroplasty complications; instead, they have been linked to a higher risk of complications., Meta-analyses have failed to reach a consensus on the subject.,
Dermatologists used estrogen therapy to restore skin elasticity. Several studies report the beneficial effects of estrogen on wound healing., Estrogen acts on different phases of wound healing; it decreases the activity of neutrophil-derived elastase, degrades proteins such as fibronectin, and decreases collagen deposition. It also facilitates wound repair by synthesizing factors like transforming growth factor β and laminin that promote wound healing., An experimental study concluded that estrogen facilitates penile wound healing by upregulating vascular-derived endothelial factors.
Repair of proximal hypospadias is complex and often requires multiple stages. This study found no significant difference in the occurrence rate or severity of urethrocutaneous fistula between the estrogen and control groups. In a similar study on severe hypospadias repair, Gorduza et al. observed lower complication rates following preoperative topical promesterine than a placebo.
Neourethral stricture is more common following skin flap repair than urethral plate repair. The stricture was reported in 8% to 12% cases following Byar's skin flap repairs. In this series, the stricture of the neourethra was significantly high in the estrogen group. Skin flap repair was carried out in all cases. Reduced collagen degradation might cause increased strictures in the estrogen group. Further analysis of stricture histopathology may help elucidate the cause of stricture in the estrogen group. Biochemical estimation of reduced neutrophil elastase might substantiate the role of estrogen in increased collagen deposition, thereby forming strictures in the neourethra.
Estrogen affects wound healing through an increase in the vascularity of the tissues. Our study is the first to evaluate vascularity following estrogen application using histopathology and immunohistochemistry. Both in vivo and in vitro studies have demonstrated that estrogen increases angiogenesis during the repair. In an experimental study, Mowa et al. reported that estrogen enhances wound healing in the penis of rats through upregulating vascular-derived endothelial growth factors. We have calculated the CD31 receptors as a marker of microvascular density in both estrogens and the control group. The difference in MVD was not statistically significant between the groups. We have evaluated vascularity in terms of MVD only, which is not the only measure for the vascularity of a particular tissue. Cağrı Savaş et al. have found out that the hypospadias penis has a lower MVD compared to age-matched healthy controls. The MVD reduces as the severity of the hypospadias increases. However, laser Doppler flowmetry of the prepuce does not show any reduction in blood flow, although the MVD was low. Elbakry et al. reported that the MVD was higher in the inner preputial skin compared to outer preputial skin in patients with hypospadias; the wider lumen and well-developed wall in the outer prepuce compensate for the decreased number. In another study, Menon et al. reported increased vascularity of the penile skin after the preoperative use of testosterone. The increased vascularity has not translated to improved postoperative outcomes.
None of the patients showed estrogen excess features (genital pigmentation and gynecomastia) during the entire study period. Paiva et al. reported pigmentation of the genital region in 50% of the hypospadias patients who had applied topical estrogen to the genital area; it was temporary and self-resolving, with barely 9% having persisting pigmentation at 90 days. Gorduza et al. used promestriene on the hypospadias penis; the systemic effects in the treatment arm (estradiol, follicle-stimulating hormone and luteinizing hormone, gynecomastia, and bone age) were not significant compared to the control. However, we have monitored all patients for increased pigmentation and breast enlargement during and following the application of estrogen in the follow-up period. We have also obtained an endocrinology consultation for the same during the follow-up. Any patient having the features of hyperestrogenemia clinically was planned for the hormonal profile.
There were a few limitations in the study. The estrogen cream was applied on a domiciliary basis with outpatient reviews, and it is assumed that there has been due adherence to instructions by the parents/caretakers. The study did not include a pre-and post-treatment serum hormonal profile to document the effect of estrogen application. Due to logistic reasons, the histopathological study of MVD estimation could not be performed in all cases. The present study has compared the estrogen group with the control group for MVD. However, a preapplication biopsy compared to the intraoperative biopsy would have been a better method to study the increase in vascularity of the tissues mediated by estrogen. Urinary tract infection (UTI) can be a risk factor for delayed healing or disruption of the suture line in hypospadias repair. Being similar in nature, the probability of developing urinary infections was the same for both groups. However, none of the patients had febrile UTIs during the follow-up period. Patients with syndromic associations like congenital anomalies of the kidney and urinary tract and at risk for the development of UTI were excluded.
| Conclusions|| |
The application of estrogen in proximal hypospadias before surgery did not reduce the incidence of the common complications associated with the repair (fistula and glans dehiscence).
The authors would like to acknowledge the contribution of Dr. Kanishka Das, Professor, Pediatric Surgery, Dr. Subrat Ku Sahoo, Associate Prof Pediatric Surgery at AIIMS, Bhubaneswar and the nursing officers who helped randomize the patients.
Financial support and sponsorship: Nil.
Conflicts of interest: There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]