Use of parenteral testosterone in hypospadias cases
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0975-2870.160804
Objectives: The aim was to evaluate the effect of parenteral testosterone on penile length, preputial hood, vascularity of dartos pedicle in patients with hypospadias. Materials and Methods: A total of 42 patients with hypospadias were included in this study. Injection aquaviron (oily solution each ml containing testosterone propionate 25 mg) was given deep intramuscularly in three doses with an interval of 3 weeks before reconstructive surgery at the dose of 2 mg/kg body weight. Preoperatively penile length, transverse preputial width and diameter at the base of the penis were measured. Basal testosterone levels were obtained before the institution of therapy and on the day of operation. Results: Following parenteral testosterone administration, the mean increase in penile length, transverse preputial width and diameter at the base of penis was 1.01 ± 0.25 cm (P < 0.001), 1.250 ± 0.52 cm and 0.61 ± 0.35 cm, respectively, (P < 0.001). Serum testosterone level after injection was well within normal range for that age. Conclusion: Parenteral testosterone increased phallus size, diameter and prepuce hypertrophy without any adverse effects. However, due to lack of a control group we cannot make any inferences. Controlled studies are required to establish the benefits of parenteral testosterone. Keywords: Hypospadias, microphallus, parenteral testosterone
Hypospadias is defined as the spectrum of an abnormal ventral urethral meatus, an abnormal ventral penile curvature (chordee) and a deficiency of ventral preputial skin. [1] Hypospadias results from the partial or complete failure of urogenital folds to develop throughout their normal length and also if the urethral folds fails to close distally if they have formed. The extent of the closure determines the position of the urethral orifice. A unifying etiology for hypospadias remains elusive and is likely multifactorial. [2] Hypospadias surgical procedure is characterized by three steps:
Testosterone/DHT is the peripherally acting androgens causing growth and development of the external genitalia and secondary sexual characters. The effect is more pronounced on the genitals as a result of higher expression of androgen receptors. This is the basis of using preoperatively androgen stimulation in hypospadias surgery. With genital repairs being accomplished in younger patients, the use of preoperative parenteral testosterone for temporary penile stimulation allows the surgeon to operate on a larger and more vascularized organ. This is especially useful in those with a paucity of penile skin, and those who have undergone failed hypospadias surgery. [3] However, there is no consensus in the literature regarding the choice of hormone, time, dose and route of administration. In the present study, we intended to analyze the effect of parenteral testosterone in cases of hypospadias.
This prospective study was conducted at Department of Urology. A total of 42 patients of hypospadias aging from 6 months to 4 years with variable degree of chordee were included in the study. Of 42 cases, 22 were of distal (7 coronal, 8 subcoronal, 7 distal penile), 10 of middle (3 midshaft, 7 proximal penile) and 10 were of proximal hypospadias (8 penoscrotal and 2 perineal). Institutional Ethical Committee approval was taken prior to commencement of the study. Parents/guardians were informed about the risks and benefits associated with the study, and written consent was taken. Family history and siblings history was taken in details for any congenital disorders. Antenatal history was also taken so as to confirm any maternal history of steroids intake. Basal testosterone levels were obtained before the institution of therapy and on the day of operation. Serum testosterone levels were also checked during follow-up after 1-year. Injection aquaviron (oily solution each ml containing testosterone propionate 25 mg) was given deep intramuscularly at 3 weeks interval in three doses before reconstructive surgery at the dose of 2 mg/kg body weight. Stretched penile length was measured from the pubic symphysis to the tip of the glans using measuring scale. Transverse preputial width was measured using measuring scale and diameter at the base of the penis was measured using a vernier caliper before the therapy and the surgery. Bone age was evaluated by examining wrist radiograph during follow-up. Side effects such as development of fine pubic hair, acne, aggressive behavior and delayed bone age were evaluated during the study and follow-up.
The mean age of presentation was 2.6 years (range, 6 months to 4 years). 17 patients were between 6 months and 1-year of age. There were 10 patients between 1-year of age and 2 years. 15 patients were between 2 years and 4 years of age. There was familial incidence found in 7 cases. Of these, 3 patients had his elder brothers, and two children had their first cousins suffering from hypospadias. Undescended testis and congenital hernia was found in 5 and 3 children's, respectively. There was patent ductus arteriosus in one case, and horse shoe kidney was present in another child. The mean penile length of 2.35 ± 0.75 cm increased to 3.36 ± 1.12 cm. The mean increase in penile length was 1.01 ± 0.25 cm (P < 0.001). The mean increase in transverse preputial width and diameter at the base of the penis was 1.250 ± 0.52 cm and 0.61 ± 0.35 cm, respectively (P < 0.001). The mean increase in serum testosterone level was 3.75 ± 0.56 ng/ml (P < 0.001) [Table 1].
Tubularized incised plate technique was used for repair of distal hypospadias cases whereas Duckett onlay preputial flap technique was used for proximal hypospadias cases. In Perineal hypospadias cases, in addition to Duckett's repair, the scrotal skin was also used. Two patients developed fistula, and one case had meatal stenosis. No flap necrosis was seen. An overall complication rate was 7.1%, which is significantly less as compared to available reported literature [Table 2]. [4],[5],[6],[7]
Of 42 patients, 28 patients followed-up to 2 years, and 8 patients got operated in the last 6 months. Of total 42 cases, 6 patients were lost to follow-up. Of the 15 patients who were in the age group between 2 and 4 years, 2 patients had aggressive behavior as noticed by the parents and 2 patients had minimal pubic hair growth. At 2 years follow-up, there was no linear growth difference was seen.
Hypospadias being one of the most common genital anomalies in male newborns have an incidence of 1:300. Hypospadias is defined as an anomaly (hypo- or dysplasia) involving the ventral aspect of the penis. These malformations mainly comprise of an abnormal ventral opening of the urethral meatus, an abnormal ventral curvature of the penis (chordee) and/or an abnormal distribution of the foreskin. [8] Hypospadias surgery was always regarded as nonrewarding surgical reconstruction; due to higher complication rate and repeated failures. To improve success rates, the use of hormonal stimulation before surgical intervention has been accepted as a relatively common practice among pediatric urologists and surgeons for decades. Previous studies have revealed increase in penile length, glans circumference and tissue vascularity with the use of testosterone, DHT and human chorionic gonadotropin (hCG). A growing body of literature has raised concerns regarding the potential negative side effects associated with this practice. [3],[6],[9],[10] Historically, hypospadias repair was considered multistage approach. With the concept of single stage repair, there were more complication rates and re-intervention rate [Table 3]. [11],[12],[13],[14]
Several studies has been conducted to assess the role of preoperative endocrine therapy but none gave conclusive results, and it's still unclear whether to give preoperative endocrine therapy or not. In a study conducted by Ahmad et al., 23 patients aged between 6 months and 10 years, preoperatively testosterone was given deep intramuscular in three doses at 4, 3 and 2 weeks before reconstructive surgery at the dose of 2 mg/kg body weight and concluded that parenteral testosterone can be safely used to improve the surgical outcome of hypospadias repair. [15] Koff and Jayanthi in 1999 conducted a study of 12 patients with proximal hypospadias and severe chordee and administered a 5 weeks course of hCG at the dose of 250 IU and 500 IU injected twice weekly in boys younger than 1-year, and 1-5 years old, respectively, immediately preceding hypospadias repair. They concluded that hCG pretreatment in infancy produces disproportional penile enlargement, which advances the meatus distally to decrease the severity of hypospadias and chordee. However, there were no standard protocols for use of gonadotropins. [6] The use of testosterone compounds in patients with a genital defect is not a new concept. Testosterone and DHT cream have been used previously. Local or systemic application of testosterone is reported to stimulate penile growth. Intramuscular testosterone has been found to be effective in 50% of patients; however, variable results have been reported with topical testosterone. Chalapathi et al. [9] compared the topical use of testosterone and parenteral testosterone and concluded that desired therapeutic effect of testosterone was achieved in both the groups, however, no statistical difference was noted in either group. The basal serum testosterone was within the normal range in both the groups. Linear growth did not alter significantly for chronological age, but the authors observed that there was evidence of unpredictable absorption of testosterone in a topical group. Although the study was done on small number of children, it does appear that intramuscular administration of testosterone is preferable. Similar results were reported by Nerli et al. [16] in a randomized study of 21 patients with microphallic hypospadias. Bastos et al. have reported that topical testosterone application produces neovascularization (by increasing the number of blood vessels and blood vessel volume density) and have postulated better surgical outcome due to better cellular oxygenation during healing. [17] Netto et al. in their meta-analysis study have clearly mentioned the widespread use of hormonal therapy in hypospadias cases although infrequently reported, but they have insisted on large volume controlled randomized studies to establish a standard protocol. [18]
Preoperative parenteral testosterone therapy was associated with an increase in phallus size and diameter with no adverse effects. There was associated increased vascularity and pliability. However, our study had limitations due to small series without a control group. Studies with larger sample sizes and control groups are required to establish the efficacy of parenteral testosterone in hypospadias.
[Table 1], [Table 2], [Table 3]
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