Can Testosterone Alter the Degree of Hypospadias? A Comprehensive Study.

CONTEXT: In this study, we observed using serial injections of parenteral testosterone whether we can alter the degree of hypospadias. AIMS: The aim was to study the effect of testosterone on different parts of the phallus in hypospadias and to see if we can alter the degree of hypospadias. SETTINGS AND
DESIGN: This was a prospective observational study. SUBJECTS AND METHODS: Forty-five boys with proximal and mid-penile hypospadias below the age of puberty who did not have prior testosterone injection or surgery were recruited in this study for the duration of 1 year and given testosterone injection intramuscularly and measurement taken using Vernier caliper at regular interval followed by surgery. The follow-up was at the 1st, 3rd, and 6th months of surgery.
RESULTS: Of 45 patients who received intramuscular testosterone injections, 40 showed some degree of response. Of these 40 patients, 23 showed a significant improvement in phallic size, whereas 17 showed a clinically insignificant response only. Of these 23 patients, 14 improved from a mid-penile to a distal penile hypospadias, whereas 7 improved from proximal penile to mid-penile hypospadias, and 2 showed an exceptionally good response and improved from proximal penile to distal penile hypospadias, whereas 5 patients exhibited no response at all.
CONCLUSION: Through this study, we can conclude that intramuscular testosterone can be effective in some patients with proximal and mid-penile hypospadias to convert them into either mid- or distal penile hypospadias by the differential response of different parts of the phallus, and this may favorably alter the type of procedure required for the hypospadias repair. Copyright:

INTRODUCTION

Hypospadias is one of the most common congenital anomalies found in the world, with an incidence of 1 in 300 live births.[1]

Surgical repair of hypospadias has always been a challenging surgical proposition. The main goals of repair are good cosmesis and function with the least complications. The common complications of such repairs are urethrocutaneous fistula (most common), meatal stenosis, persistent chordee, poor cosmesis, etc. Androgen stimulation is sometimes used to increase the penile size before hypospadias correction. It has been found that androgen stimulation makes the penis more vascular, increases the size of the penis, and thus maximizes the chances of a better surgical outcome. Both systemic and topical applications can be used for stimulation. It was observed in our initial cases that the effect of the administered androgens was not uniform along the whole length of the phallus. The normal portion of the phallus and the abnormal portion of the phallus were observed to be responding differently.

Hence, this study was designed to objectively observe the differential effect of parenteral testosterone on the phallus in a hypospadias penis which could prove useful in converting a proximal hypospadias into a distal one which could be repaired more easily.

The aim of this study was to investigate and document this differential effect, if any, of androgens on the different parts of the hypospadias phallus. This study studied the effects of injectable androgens on:

Effect on the size of the hood

Effect on the glans

Effect on the length and diameter of the phallus distal to the hypospadiac meatus

Effect on the length and diameter of the phallus proximal to the hypospadiac meatus

To compare the differential response of the various types of tissues to the testosterone injections.

SUBJECTS AND METHODS

Study area

Patients below the age of puberty having hypospadias without prior testosterone injections or surgical interventions coming to the Pediatric Surgery OPD, JEHANGIR HOSPITAL,Pune.

Sample size calculation

The sample size was determined using the effect sizes from the previously published study (Tomohiro Ishii et al., Urology [2010]) and with the help of the following formula:

Where n = sample size

tv, p= Student's “t” quartile with “v” df and probability P = 1.96

a = 0.05 (5.0%) fixed

β = 0.20 (80.0% power)

tb= Cutoff value for power (1− β) = 0.842

d = Delta/SD = 0.45 (estimated difference per unit SD)

Delta: Estimated difference in pre- and posttreatment means to be detected (stretched penile length [SPL])

SD = Estimated standard deviation (SD) of paired difference

Thus, the required sample size after adding up above values is ≅ 39 (rounded off to the closet integer)

After considering 10% dropout rate, the required sample size would be = 39/0.90 = 43 (minimum).

Sampling technique: Convenience sampling.

Statistical data analysis

The data on categorical variables would be presented as n (% of cases), and the values on continuous variables will be presented as mean ± SD. The significance of difference of distribution of incidence of occurrence (if any) would be tested using Chi-square test. Paired t-test would be used to test the significance of difference between pre- and posttreatment outcome variables (such as size of hood, glans, penile length, and diameter). The underlying assumption of normality would be tested before subjecting the parameters to t-test. P <0.05 would be considered to be statistically significant. All the hypotheses would be formulated using two-tailed alternatives against each null hypothesis (hypothesis of no difference). The entire data would be statistically analyzed using the Statistical Package for the Social Sciences (version 16.0, IBM Corporation, NY; USA) for MS Windows.

Study design

This was a prospective observational study.

Inclusion criteria

Patients who had mid- and proximal penile hypospadias

Patients who had not reached the age of puberty

Patients who not underwent any hypospadias repair surgery previously

Patients who had not received any prior testosterone injection

Patients who or his parents were willing to be included in study

Length of phallus <28 mm

Size of glans <8 mm.

Exclusion criteria

Patients above the age of puberty

Patients who underwent some surgical repair in the past

Patients who had taken prior testosterone injection

Those patients who were not willing for testosterone injection

If any patient demonstrated an allergic response to testosterone.

Method

All measurements were taken with Vernier calipers [Figure 1] applying the jaws ever so gently onto the tissues. Intramuscular testosterone depot preparation (containing testosterone propionate, testosterone phenylpropionate, testosterone isocaproate, and testosterone decanoate) was given in a dose of 2 mg/kg [Flowchart 1].

Figure 1

Penile measurement using Vernier caliper

Flowchart 1

T1-1st: Testosterone injection, M1: Measurement before 1st injection, M2: Measurement before 2nd injection, T2-2nd: Testosterone injection, M3: Measurement before 3rd injection, T3-3rd: Testosterone injection, Ms: Measurement before surgery, T4-4th testosterone injection IR: Inadequate response

RESULTS

After completing the course of testosterone injections, the findings before [Tables 1, 2 and Figure 2] and after [Tables 1,3 and Figure 3] testosterone were as follows:

Table 1

Response to testosterone

Response to testosterone	Number of patients
Responders	40
Nonresponders	5
Total	45

Table 2

Distribution of hypospadias before testosterone

Type	Number of cases (%)
Proximal	31 (68.9)
Mid	14 (31.1)
Distal	0 (0.0)
Total	45 (100.0)

Figure 2

Proximal hypospadias before testosterone stimulation (M1)

Table 3

Distribution of hypospadias after testosterone

Type	Number of cases (%)
Proximal	22 (48.9)
Mid	7 (15.5)
Distal	16 (35.6)
Total	45 (100.0)

Figure 3

Distal penile hypospadias measured at surgery posttestosterone stimulation (stretched using glans suture) (Ms)

Of these 40 patients who responded, 23 patients (58%) showed more phallic growth proximal to the meatus than the rest of the phallus distal to the meatus. Of these 23 patients who showed the above differential growth, 7 patients (18%) got converted from proximal penile to mid-penile hypospadias, whereas 14 patients (36%) got converted from mid-penile to distal penile hypospadias, and 2 patients (5%) showed an exceptional response converting from proximal penile to distal penile hypospadias [Table 4].

Table 4

Conversion of type of hypospadias after testosterone stimulation

Type of hypospadias	Before testosterone	After testosterone
Proximal	31	22
Mid	14	7
Distal	0	16

The distribution of mean ± SD of mean hood width before and after the testosterone treatment was 22.33 ± 4.51 mm and 28.06 ± 6.89 mm, respectively. The distribution of mean ± SD of mean hood length before and after the testosterone treatment was 19.22 ± 3.60 mm and 24.20 ± 5.22 mm, respectively

The distribution of mean ± SD of mean SPL before and after the testosterone treatment was 16.87 ± 3.96 mm and 26.07 ± 6.99 mm, respectively

The distribution of mean ± SD of mean penile length from scrotum to meatus before and after the testosterone treatment was 7.02 ± 2.35 mm and 12.93 ± 4.85 mm, respectively, and the mean penile length from meatus to tip before and after the testosterone treatment was 9.91 ± 2.28 mm and 13.13 ± 4.74 mm, respectively

The distribution of mean ± SD of mean mid-penile diameter before and after the testosterone treatment was 5.40 ± 1.00 mm and 7.80 ± 2.55 mm, respectively. The distribution of mean ± SD of mean glans width before and after the testosterone treatment was 6.84 ± 1.15 mm and 9.91 ± 2.77 mm, respectively

The distribution of mean ± SD of mean urethral plate width at glans before and after the testosterone treatment was 2.98 ± 0.81 mm and 4.38 ± 1.37 mm, respectively. The distribution of mean ± SD of mean urethral plate width at meatus before and after the testosterone treatment was 1.29 ± 0.46 mm and 2.20 ± 0.79 mm, respectively

The mean change along with 95% confidence interval of mean change in the SPL, penile length from meatus to tip and from scrotum to meatus, hood width, hood length, urethral plate width, and depth at meatus showed a significant growth with P < 0.001 [Table 5].

Table 5

Distribution of penile measurements before and after testosterone treatment

Parameters	Mean±SD		Difference (after-before)		P
	Before	After	Mean	95% CI of mean
Hood width (mm)	22.33±4.51	28.06±6.89	5.73	3.29-8.17	0.001***
Hood length (mm)	19.22±3.60	24.20±5.22	4.98	3.09-6.86	0.001***
Stretched penile length (mm)	16.87±3.96	26.07±6.99	9.20	6.82-11.58	0.001***
Penile length from scrotum to meatus (mm)	7.02±2.35	12.93±4.85	5.91	4.31-7.51	0.001***
Penile length from meatus to tip (mm)	9.91±2.28	13.13±2.74	3.22	2.16-4.28	0.001***
Mid-penile diameter (mm)	5.40±1.00	7.80±2.55	2.40	1.59-3.21	0.001***
Glans width (mm)	6.84±1.15	9.91±2.77	3.07	2.18-3.95	0.001***
Urethral plate depth (mm)	2.02±0.81	2.98±1.23	0.96	0.52-1.39	0.001***
Urethral plate width at glans (mm)	2.98±0.81	4.38±1.37	1.40	0.93-1.87	0.001***
Urethral plate width at meatus (mm)	1.29±0.46	2.20±0.79	0.91	0.64-1.18	0.001***

P value by paired t-test. P<0.05 is considered to be statistically significant. ***P<0.001 (statistically highly significant). SD: Standard deviation, CI: Confidence interval

The details of the types of operations actually done have not been explained here as that was not the aim of this study. All patients were operated by single-stage repair procedures. It was observed that before testosterone stimulation, 40 patients were deemed to be needing a proximal hypospadias repair procedure, whereas only 5 patients were thought to require a distal hypospadias repair procedure. However, after testosterone stimulation, we could operate 19 patients by distal hypospadias repair procedure which is much simpler [Table 6].

Table 6

Change in surgical repair posttestosterone stimulation

Surgical repair (all single stage repairs)	Deemed procedure before stimulation	Actual procedure done poststimulation
Proximal hypospadias repair procedure	40	26
Distal hypospadias repair procedure	5	19
Total	45	45

DISCUSSION

The surgical correction of hypospadias has been taxing the skills of many generations of surgeons. The more than 275 operations bear testimony to the fact that no single operation gives uniformly good results. Testosterone has been used in select cases for hormonal stimulation before surgical repair since many decades. Being on the “Learning Curve of Hypospadias Surgery” as described by Keating et al.,[2] every effort is made to maximize the results of single-stage repairs. This prospective study was conducted to study the effect of testosterone on different parts of phallus which hitherto has not been extensively studied in a systematic manner.

Hormone therapy preceding surgical correction of hypospadias has been proposed to obtain better healing conditions, such as a bigger and more vascular penis to reduce surgical complications.[3] However, there is no consensus in literature on which is the ideal hormone, the time and dosage to be used, and the appropriate route of administration.[4567891011] In a recent systematic review on hormone therapy before hypospadias surgery, Netto et al. identified 14 studies on the subject, with only three being randomized controlled trials and most of low quality.[3]

According to a survey conducted by Malik and Liu, 67%–87% of surgeons who operate on hypospadias use testosterone stimulation before surgery, and the main indications are proximal hypospadias, small-appearing penis, reduced glans circumference, or reduced urethral plate.[12]

With an increase in the total penile length, one would surmise that the distance from the hypospadiac meatus to the tip of the glans would also change, but in unsubstantiated observations made by us before the commencement of this study, it was found that the distance from the meatus to the tip did not increase proportionately with the entire phallus. Consequent to this observation that as the penis becomes longer, but the distance from the meatus to the tip of the glans remains the same, the hypospadias actually becomes more distal than it was before treatment.[13] Koff and Jayanthi, evaluating the use of human chorionic gonadotropin, suggested that there is a disproportional increase with a greater increase in tissues proximal to the hypospadias meatus.[14] No other studies have till date objectively evaluated the growth of the phallus from the penoscrotal junction to the meatus with testosterone. In our study, we included this measurement as well as urethral plate measurements at different parts, and we confirmed that the phallus proximal to the meatus grows more than the part of the phallus distal to the meatus; thus, we could convert a proximal penile hypospadias to mid-penile or distal penile and also a mid-penile hypospadias to a distal one. This study was designed to test the clinical application of this hypothesis.

Stretched penile length

In our study, all the patients were given intramuscular testosterone depot preparation, and it was observed that 40 patients who received parenteral testosterone showed an increase in phallic size. Of these 40 patients, 23 patients showed enhanced phallic growth proximal to the meatus than the rest of the phallus distal to the meatus. Of these 23 patients, 7 patients got converted from proximal penile to mid-penile hypospadias, whereas 14 patients got converted from mid-penile to distal penile hypospadias, and 2 patients showed an exceptional response converting from proximal penile to distal penile hypospadias.

Feldman and Smith[15] noticed that a small phallus in hypospadias is a result of fetal testosterone insufficiency. To enlarge penile size, temporary stimulation with testosterone or dihydrotestosterone cream has been used; however, the results were not only inconsistent, but absorption was also variable.[10]

Paiva et al. demonstrated that testosterone increases penile length and diameter, as well as the diameter of the glans.[13]

Growth in stretched penile length proximal to meatus compared to the length distal to meatus

Forty patients who received parenteral testosterone showed an increase in phallic size. Of these 40 patients who responded, 23 patients (58%) showed more phallic growth proximal to the meatus than the rest of the phallus distal to the meatus.

Of these 23 patients who showed the above differential growth, 7 patients (18%) got converted from proximal penile to mid-penile hypospadias, whereas 14 patients (36%) got converted from mid-penile to distal penile hypospadias, and 2 patients (5%) showed an exceptional response converting from proximal penile to distal penile hypospadias.

Koff and Jayanthi, evaluating the use of human chorionic gonadotropin, suggested that there is a disproportional increase with a greater increase in tissues proximal to the hypospadias meatus.[14]

Paiva et al. conducted a study with 75 patients and made an observation that with an increase in SPL, there was no or only minimal increase in the penis from meatus to tip, and thus, they hypothesized that as the penis is longer and the distance from the meatus to the tip of the glans is the same, the hypospadias became more distal than it was before treatment. However, they did not objectively measure the growth in SPL from scrotum to meatus.

Glans width

We observed a mean increase in glans width of 3.07 mm in testosterone responders.

Luo et al. also found that the use of parenteral testosterone 25 mg IM once monthly for 3 months preoperatively had increased the glans circumference significantly with no significant side effects.[10]

Nerli et al.[16] found an impressive increase in glans circumference and penile size with testosterone prestimulation.

Urethral plate width

We observed a significant increase in the urethral plate width (mean 1.37 mm) both at the meatus and at the level of the glans; however, no significant differential growth was found to be more at glans than the meatus. It is pertinent to add that the measurement at the meatus level could not be accurately estimated because of the circular configuration of the meatus; hence, no significant conclusion can be drawn about the differential effect on the width of the urethral plate.

In contrast, Paiva et al.[13] noticed that the width of the urethral plate showed no difference between the control group, testosterone group, and estradiol group, but when they measured the proximal and distal plates separately, they observed that the proximal portion of the urethral plate tends to increase its width with the use of testosterone.

Holland and Smith[17] observed the effect of the depth and width of the urethral plate on tubularized incised plate urethroplasty where they noticed that a urethral plate width <8 mm was associated with higher rates of urethrocutaneous fistula. They noticed that a urethral plate width of more than 8 mm gave a good result.

We also observed good response in hood length, hood width, and mid-penile diameter also.

CONCLUSION

Nowadays, testosterone stimulation before selected cases of hypospadias repair is becoming a standard of care. The length of the phallus from the meatus to the scrotum grew more than from the meatus to the tip, and thus, in testosterone responders, we could convert proximal and mid-penile hypospadias into distal ones, thus rendering single-stage repair of hypospadias more easily possible. In effect, the normal part of the hypospadias phallus (proximal to the meatus) responded better to testosterone than the abnormally developed part (distal to the meatus). As a result of androgen stimulation, we could alter the degree of hypospadias and could use relatively easier and more convenient techniques for hypospadias repair to achieve better outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.