Effect of Preoperative Androgen Stimulation on Penile Size and Postoperative Complication Rate in Patients with Hypospadias: A Systematic Review and Meta-Analysis

Abstract

Purpose

To systematically review and evaluate the beneficial effects of preoperative androgen stimulation (PAS) on penile length, glans width, and postoperative complications in patients with hypospadias using meta-analysis.

Materials and Methods

A comprehensive search of the published literature between 1980 and 2022 was done on PubMed, Embase, Google Scholar, Scopus, Web of Science, and Proquest. Studies of patients with 5-alpha reductase deficiency, differentiation sex disorder, or micro-penis without hypospadias were excluded. The full-text screening, quality assessment, and data acquisition were done independently by two reviewers. Meta-analysis was done to quantify the penile growth and postoperative complications.

Results

The initial literature search yielded 2,389 records, wherein 32 studies were eligible for the systematic review and meta-analysis. Preoperative testosterone stimulation increased the penile length and glans width by 9.34 mm (95% CI: 6.71–11.97) and 3.26 mm (95% CI: 2.50–4.02), respectively. A longer penis at the baseline led to greater length gain following treatment (1 mm longer at the baseline was likely to gain 0.5 mm more). However, the increase in penile length was not associated with the severity of hypospadias. While the treatment did not affect the overall complication rate, the postoperative fistula risk was lower in those receiving PAS (RR=0.52, 95% CI: 0.30–0.91, p=0.02).

Conclusions

The beneficial effects of PAS on increasing the penile length and glans width were again confirmed. More gain of penile length was expected in the larger penis at baseline. There are no reported increased postoperative complications in association with PAS.

INTRODUCTION

Hypospadias is a common male genital birth defect wherein the urethral meatus is abnormally displaced ventrally instead of at the tip of the glans [1]. Small glans size [2] or proximally located urethral meatus [3] could make surgical repair challenging. Preoperative androgen stimulation (PAS) has been applied to increase the glans width [4, 5] and promote local vascularity [4, 6], which is believed to improve surgical outcomes. However, the application of PAS still remains controversial.

The beneficial effects of PAS on penile biometric changes were revealed in dozens of reports. PAS could increase the penile length [4, 7, 8] and glans size [4, 5, 7, 9] in patients with a small penis and all types of hypospadias. Several reviews [10, 11] were done on these topics and reported increases in size, but no quantitative data have been reported on the amount of the increase in penile length and glans width following PAS.

Meanwhile, several studies attempted to show that PAS could prevent postoperative complications [8, 12, 13]. However, others demonstrated that PAS could increase [4, 14] or had no effect [15] on the complication rate. Concerns about the detrimental effect of PAS on tissue healing were also raised in animal studies, wherein androgen could promote inflammatory response and inhibit the wound recovery process [16, 17]. Thus, whether PAS can reduce the postoperative complication rate is undetermined [18, 19, 20]. Several meta-analyses attempted to assess the overall postoperative complication rate [19, 20, 21, 22], but the risk of individual complications such as fistula, wound dehiscence, and stenosis was scantily studied. Therefore, it is necessary to uncover the role of PAS on postoperative complications in patients with hypospadias.

To address these concerns mentioned above, we performed a systematic review and meta-analysis to determine the beneficial effects of PAS on penile length, glans width, and the risk of several major postoperative complications such as fistula, wound dehiscence, and stenosis in patients with hypospadias.

MATERIALS AND METHODS

1. Search strategy

We comprehensively searched the published literature between 1980 and 2022 on PubMed, Embase, Google Scholar, Scopus, Web of Science, and Proquest. The search terms were hypospadias AND (hormone therapy OR testosterone OR androgen OR dihydrotestosterone OR hormone stimulation OR hormonal stimulation). Filters were time (1980–2022), original article, human, clinical, English, journal article, and male.

2. Eligible criteria

Studies of hypospadias patients aged <18 years who underwent PAS regardless of hormone type or delivery route were included. The results must include at least one of the target variables: changes in penile length, glans width, or postoperative complication rate. Studies of patients with 5-alpha reductase deficiency, disorders of sexual differentiation, or micro-penis without hypospadias were excluded.

3. Screening, assessment, and evaluation of studies

The records were imported to Endnote for title screening, wherein irrelevant studies were removed. To reduce selection bias, the abstract and full-text screening and quality assessment were done independently by two reviewers (MTD and LK). The disagreements on study inclusion were resolved with consensus. Study quality assessment for studies of the changes in penile size was performed using the “NIH quality assessment tool for before-after (Pre-Post) studies with no control group” [23]. Study quality assessment for two-arm trials was done according to the Cochrane collaboration recommendation using the risk of bias assessment tools: ROBINS-I for non-randomized controlled studies [24] and RoB 2 for randomized controlled trials (RCTs) [25].

4. Data synthesis

The increase in penile length and glans width following PAS was expressed as a mean difference. The glans was assumed round. Therefore, the glans circumference was reported, and the width was calculated by dividing the circumference by 3.14. When a missing mean or standard deviation (SD) exists, data was converted and imputed according to Cochrane’s recommendation [26]. The formulas for conversion and imputation were described in detail in the Supplement File. The risk ratio (RR) was used to assess the complication rate. In this study, postoperative complications were fistula, wound dehiscence, diverticula, and stenosis. Proximal hypospadias included proximal penile, penoscrotal, scrotal, and perineal hypospadias [27].

5. Assessment of heterogeneity and publication bias

Subgroup analysis was used to explore the sources of heterogeneity. Moreover, meta-regression was done to evaluate the effect of pretreatment penile size and proportion of proximal hypospadias on penile growth. Publication bias was assessed using Egger’s test.

6. Statistical analysis

Meta-analysis was conducted when appropriate using Stata (version 16.0; StataCorp L.P., College Station, TX, USA). The random-effects method was used in case of significant heterogeneity between studies (I²>50%). Otherwise, the fixed-effect was used. Meta-regression was done with a single covariate. Statistical significance was set at a p<0.05.

7. Ethics statement

This systematic review and meta-analysis did not involve human subjects or animals, so ethical approval was not required. This study was registered in the international database of prospective systematic reviews (PROSPERO, https://www.crd.york.ac.uk/prospero/). The registration number is CRD42022308539.

RESULTS

1. Search results

The initial literature search yielded 2,389 records. A total of 365 duplicated records were excluded automatically. Following an advanced search in reference management software (EndNote), 1,856 ineligible records were identified and excluded. Next, 37 duplicated records were found manually and excluded, leaving 131 records for screening. Title and abstract screening led to the exclusion of 84 records, and content screening led to the exclusion of 15 studies. Eventually, 32 studies were eligible for the systematic review and meta-analysis (Fig. 1).

Fig. 1 The PRISMA flow diagram of the included studies. DSD: disorders of sexual differentiation

2. Characteristics of included studies

A total of 1,328 patients were included, with a mean sample size was 37. RCTs accounted for about one-fourth of studies, while case series made up the most. Nine studies did not provide a classification of hypospadias. Small penis and severe hypospadias were mentioned as an indication of PAS, but half of the studies did not state the indication for PAS. Regarding hormones applied in PAS, testosterone was used the most, accounting for about 80% of 39 trials. Dihydrotestosterone, human chorionic gonadotropin, or combined hormone was scantly prescribed. Regarding delivery route, more than half of the trials were intramuscular (IM). PAS was used with various regimes, wherein testosterone injection once a month for three months or daily application for two or three months was prescribed most frequently (Table 1, Supplement Table 1).

Table 1 Summary of included studies

3. Penile length

The increase in penile length was assessed in 21 studies [4, 7, 8, 9, 12, 15, 22, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41], wherein 15 [4, 7, 8, 9, 12, 22, 28, 29, 30, 31, 32, 33, 34, 35, 38] were available for meta-analysis. All of the included studies used testosterone. Most of the studies had a good or fair quality (Supplement Table 2). The missing SD was imputed in six studies (Table 2). The total number of patients was 602.

Table 2 Changes in penile length and glans width following preoperative testosterone stimulation

There was a high between-studies heterogeneity (I²=98.40%). PAS using testosterone increased the penile length significantly by 9.34 mm (95% confidence interval [CI]: 6.71–11.97) (Fig. 2). The increase in RCTs was 7.36 mm, whereas it was 10.33 in non-RCTs. However, it was not statistically different (Supplement Fig. 1A). Subgroup analysis by delivery route showed that the effect of IM did not differ from topical or oral use (Supplement Fig. 1B). The pooled analysis of studies using the same protocol of PAS (IM testosterone, 2 mg/kg, once a month for three months) showed an increase of 10.24 mm (Supplement Fig. 2). A longer penis at the baseline was associated with a larger increased length following PAS (Fig. 3). Penis with 1 mm longer at the baseline was likely to gain a greater increase in penile length by 0.5 mm (coefficient=0.52, p=0.006). However, increased penile length was not dependent on the proportion of severe hypospadias in included studies (Supplement Table 3). The results of Egger’s test revealed no evidence of small-study effect (intercept=0.92, p=0.59).

Fig. 2 Forest plot showing the increase of penile length after preoperative testosterone stimulation (15 studies). IM: intramuscular.

Fig. 3 Bubble plot of the increased penile length against pretreatment penile length. Each study is represented by a bubble, with the sizes of the bubbles proportional to the weight assigned to the studies: the larger the weight, the larger the bubble. The line represents the association between the increased penile length and the penile length at baseline.

4. Penile glans width

The increase in the glans width following PAS was assessed in 12 studies, wherein all used testosterone [4, 5, 7, 9, 22, 28, 29, 31, 32, 33, 35, 42] (Table 2). Most of the studies had a good or fair quality (Supplement Table 2). There was a significant between studies’ heterogeneity (I²=98.07%). PAS with testosterone increased the penile glans width by 3.26 mm (95% CI: 2.50–4.02) (Fig. 4). This increase did not differ between RCTs and non-RCTs (Supplement Fig. 3A) or hormone delivery routes (Supplement Fig. 3B). Additionally, neither baseline glans size nor the proportion of proximal hypospadias affected the increase in glans width in the meta-regression analysis (Supplement Table 3). The results of Egger’s test revealed no evidence of small-study effect (intercept=0.28, p=0.83)

Fig. 4 Forest plot showing the increase of glans width after preoperative testosterone stimulation (12 studies). T: testosterone, IM: intramuscular.

5. Complication rate

The complication rate was assessed in 18 studies [4, 5, 8, 12, 13, 14, 15, 22, 29, 30, 37, 43, 44, 45, 46, 47, 48, 49], wherein 14 studies, including 5 RCTs [4, 5, 8, 12, 13] and 9 non-RSTs [14, 15, 22, 29, 43, 44, 46, 47, 48], were available for meta-analysis. All RCTs had some concerns of risk of bias (Supplement Fig. 4A). More than half of non-RCTs had a serious or critical risk of bias (Supplement Fig. 4B). The between studies' heterogeneity was significant in the overall complication pool (I²=80.95%, Fig. 5A) but not significant in the specific complications pool (Fig. 5B-5D). Overall, the complication rate was similar between PAS group and the control (RR=1.08, 95% CI: 0.75–1.54, p=0.68).

Fig. 5 Forest plot showing the risk of postoperative complication of hypospadias repair between PAS versus non-PAS patients (14 studies). (A) Overall complication. (B) Fistula. (C) Wound dehiscence. (D) Urethral stenosis.

The subgroup analysis by study design observed the different effects of PAS on the complication rate between non-RCTs and RCTs (Fig. 6A, 6B). However, both groups did not show any statistically significant effect of PAS on the complication rate. Among major postoperative complications (fistula, dehiscence, and stenosis), only the risk of the postoperative fistula was statistically lower in the PAS group than in control (RR=0.62, 95% CI: 0.41–0.93, p=0.02) (Fig. 5B). The pooled analysis of RCTs indicated that patients with PAS were likely to have two times fewer postoperative fistula than those without PAS. In contrast, non-RCTs showed a neutral effect (Fig. 6B). The results of Egger’s test revealed no evidence of a small-study effect (intercept=-1.54, p=0.07).

Fig. 6 Forest plot showing the risk of postoperative complication of hypospadias repair between PAS versus non-PAS patients, subgroup analysis by study design (14 studies). (A) Overall complication. (B) Fistula. (C) Wound dehiscence. (D) Urethral stenosis.

DISCUSSION

Our study showed that PAS with testosterone significantly increased the penile length and glans width. Moreover, we first found the increase in penile length is in accordance with baseline length showing the differential response to testosterone. Despite the controversy, PAS was not found to increase the overall complication rate of hypospadias. Instead, the risk of fistula appears to lessen.

Among pediatric urologists, a small-looking penis was the primary indication for the prescription of PAS for hypospadias patients [50, 51]. Indeed, PAS significantly increased the penile length by 9 mm. This was again demonstrated in the pooled analysis of the homogenous treatment protocol with IM monthly testosterone for three months resulting in a similar increase in length. This increase in penile size may be of help, allowing to construct a larger bore urethra, reducing some complications such as stricture. However, this benefit may be offset by increased urethral defect to repair that will accompany the penile lengthening. Indeed, it was reported that the length of the urethral defect was independently associated with postoperative fistula [52]. However, considering the average penile length at the baseline in our study was 25.3 mm, which is called to be microphallus or close to the lower limit of the normal range (-2.5 SD) of boys at this age [53, 54, 55], we would expect postoperative penile appearance is likely to be unsatisfactory in terms of protrusion even after complication-free repair. This postoperative concealment of the penis may cause significant cosmetic concern as the children grow. In this regard, the resultant increases in length of up to 1 cm should be taken into account as a significant benefit given the lack of importance of penile growth until entering puberty [54].

Our results also showed a higher hormonal response in the longer penis at baseline. The reason is unknown in the current study, but it might be explained by differential testosterone sensitivity. The smaller penile length at baseline may result from less response to PAS, whereas the larger one showed the reverse. We also attempted to determine whether the difference in posttreatment penile length resulted from a similar hormone response but the difference in penile length at the baseline. The result suggested the penile growth rate is larger in favor of a longer penis at baseline, supporting our claim of higher hormonal response in this group (Supplementary Fig. 5). This is somewhat disappointing because PAS is actually needed for those with a smaller penis. This could indicate differential doses or schedules may be required to elicit better responses.

Interestingly, no association was found between the proportion of proximal hypospadias and response to PAS. While we easily classified the type based on meatal location, which could be advanced or regressed following completion of the penile degloving. Thus, the classification of distal hypospadias may include those that showed significant retraction of the meatus, which requires division of the urethral plate for the straightening of the penis. This heterogeneity of classification may explain the reason for no difference in hormonal response.

PAS significantly increased the glans width by 3 mm. Even though the extent of penile growth was heterogeneous, our finding of the increase of glans width was in line with the result of a large cohort [56]. They found that the glans width increased by 4 mm following IM testosterone therapy, and two doses led to a significant increase than one dose. Small glans width was a potential risk factor for glandular dehiscence and fistula in hypospadias repair [2], so PAS could improve surgical outcomes.

Although the beneficial effect of PAS on penile growth is undeniable, its effects on reducing postoperative complications remain controversial. Some studies showed that PAS could decrease the complication rate [8, 12, 13]; others claimed contrasting results [4, 14, 43]. Animal studies indicated that PAS could promote inflammation [57] or inhibit wound healing [16, 17]. Several meta-analyses were done [19, 20, 21], wherein one [19] showed that the complication rate was in favor of the PAS group than in control. Our results of significantly lower risk of the fistula may be assumed to be consistent with these data because urethrocutaneous fistula consists of the majority of overall complications.

We acknowledge the limitations of the current study, which are inherent to meta-analysis and the context of the small number of studies with a small and mixed study population on this topic. First, the meta-analysis of the penile size used 15 single-arm studies, which can lead to an inherent bias due to a lack of a control group. However, we could assume that there is no increase in penile size in patients without PAS, as shown in the control group of RCTs [7, 12, 33]. Second, the missing SD was imputed in some studies. Although it did not change the effect size, it can affect the weight of these studies in the pooled analysis [58]. Third, we attempted to perform a meta-regression analysis of penile length and glans width with multiple covariates, which needs ten studies for each covariate [59]. However, we can only control for a single covariate (penile length at baseline or proportion of proximal hypospadias) due to the limited number of studies. Thus, we could not control the effects of other factors on penile growth, such as the dose and duration of PAS. Lastly, the high heterogeneity in the meta-analysis of penile length and glans width may affect the reliability of the pooled analysis [60]. We applied the random effects for meta-analysis, subgroup analysis, and meta-regression to figure out the source of heterogeneity, which may result from the differences in patient selection, such as age, hypospadias grade, PAS protocol, and surgical technique. Our meta-regression showed that pretreatment penile length is a factor that made the difference in the increase of penile length between studies. Despite the limitations, our efforts to deal with heterogeneity, including subgroup analysis, pooled analysis of homogenous studies, and meta-regression, have contributed to uncovering the effect of PAS on penile size and postoperative complications in patients with hypospadias.

CONCLUSIONS

The beneficial effects of PAS on increasing the penile length and glans width of patients with hypospadias were again confirmed. More gain of penile length was expected in the larger penis at baseline. PAS is not associated with increased postoperative complications.

Supplementary Materials

Supplementary materials can be found via https://doi.org/10.5534/wjmh.220173.

Supplement File

The formulas for conversion and imputation of missing mean difference and standard deviation

Click here to view.(281K, pdf)

Supplement Fig. 1

Forest plot showing the increase of penile length after preoperative testosterone (T) stimulation (15 studies). (A) Subgroup analysis by study design. (B) Subgroup analysis by delivery route. IM: intramuscular.

Click here to view.(129K, pdf)

Supplement Fig. 2

Forest plot showing the increase of penile length after preoperative testosterone stimulation with the same protocol: intramuscular (IM) testosterone, 2 mg/kg, once a month for three months.

Click here to view.(77K, pdf)

Supplement Fig. 3

Forest plot showing the increase of glans width after preoperative testosterone (T) stimulation (12 studies). (A) Subgroup analysis by study design. (B) Subgroup analysis by delivery route. IM: intramuscular.

Click here to view.(82K, pdf)

Supplement Fig. 4

Risk of bias assessment for (A) randomized control trials (5 studies) and (B) non-randomized control trials (9 studies).

Click here to view.(132K, pdf)

Supplement Fig. 5

Correlation between the penile length before and after preoperative androgen stimulation (PAS). The scatter plots show the correlation between penile length before and after PAS, the regression line (dotted line), and the correlation coefficient r. The solid line divides the pretreatment penile length into two groups with a cut-off at 25 mm. The post/pretreatment penile length of each group is shown.

Click here to view.(75K, pdf)

Supplement Table 1

Characteristics of included studies

Click here to view.(68K, pdf)

Supplement Table 2

Quality assessment for the included studies evaluating the increase of the penile length and glans width following preoperative hormone stimulation

Click here to view.(72K, pdf)

Supplement Table 3

Meta-regression analysis for the increase of penile length and glans width

Click here to view.(71K, pdf)

Notes

Conflict of Interest:The authors have nothing to disclose.

Funding:None.

Author Contribution:

Conceptualization: MTD, LK, YJI, SH, KP.

Data curation: MTD, LK, SH, KP.

Formal analysis: MTD, LK, YJI, SH, KP.

Funding acquisition: None.

Investigation: MTD, LK, KP.

Methodology: MTD, LK, YJI, SH, KP.

Project administration: LK.

Resources: MTD, LK, KP.

Software: None.

Supervision: KP.

Validation: MTD, LK, YJI, SH, KP.

Visualization: MTD, KP.

Writing – original draft: MTD, KP.

Writing – review & editing: MTD, LK, YJI, SH, KP.

Acknowledgements

The authors thank Seoul National University Hospital’s Medical Research Collaborating Center (MRCC) for their technical support for this study.

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