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Re: The Efficacy of Dihydrotestosterone Transdermal Gel Before Primary Hypospadias Surgery: A Prospective, Controlled, Randomized Study
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Re: The Efficacy of Dihydrotestosterone Transdermal Gel Before Primary Hypospadias Surgery: A Prospective, Controlled, Randomized Study C. Kaya, J. Bektic, C. Radmayr, C. Schwentner, G. Bartsch and J. Oswald J Urol 2008; 179: 684 – 688. To the Editor. I read this article with interest. However, in the purpose section of the abstract I could not find the benefit expected for patients to use one of the most potent androgens known. In the materials and methods section of the article the authors state they used dihydrotestosterone (DHT) in primary repair in mainly distal hypospadias forms. It seems difficult to further improve results that are usually reported by most authors today as excellent. In our own series of patients treated with DHT the agent was only applied in highly selected multiple redo procedures (sometimes up to 15 procedures) when no genital skin was available for urethral repair, extensive scarring was found, and known surgical techniques were limited in number and choice.1 We try to avoid hypospadias surgery in patients 2 to 4 years old, as advised by psychologists, to prevent potential psychological trauma. The patients included in this study were just within this vulnerable age range. Is it possible that by using DHT we unintentionally increase aggressiveness, as is the case in sports? Originally, the recommended usage of DHT, as described by Monfort and Lucas,2 was for a duration of 4 to 5 weeks preoperatively. I also observed the expected effect of softening the skin, as per their experience. Kaya et al did not explain why they increased the doses of DHT. Neither did they report levels of DHT in the blood. In 1985 I reported the effects of DHT local stimulation in hypospadias repair on genital skin morphology.1 It showed enormous mitotic activity, which may resemble a basal cell carcinoma pattern of the skin. These changes, although time limited, resulted in my total withdrawal of DHT from the hypospadias surgery armamentarium. Dihydrotestosterone has not been approved for treatment in Poland, as is the case in many European countries. Last but not least, the authors state that the tubularized incised plate procedure was first described in 1994 by Snodgrass,3 which is incorrect. In fact, it was described by me on several occasions 7 years earlier.4,5 Respectfully, Marek Orkiszewski Department of Pediatric Surgery and Traumatology Regional Children’s Hospital Collegium Medicum Nicolaus Copernicus University Torun, Poland To the Editor. Kaya et al deserve commendation for their contribution to the medical literature regarding the role of supplemental androgens in the management of hypospadias. The current study represents a significant link between what, in our opinion, is a relatively common practice of androgen supplementation and the evidence that such
therapy actually improves outcomes. While it has been suggested for the last 3 decades that androgen supplementation will decrease complications, the authors describe the only well designed, prospective study in the current literature to support this claim. One considerable area where this study failed to advance our understanding of hypospadias repair is in the selection of patients most likely to benefit from hormonal supplementation. The mean age of the patients enrolled in the study was nearly 3 years, with boys up to 13 years being included in the evaluation. It is noteworthy that most of the patients had mild hypospadias, with 77% having a coronal location of the meatus. Based on the previous literature, which supports the use of hormonal stimulation in proximal hypospadias and microphallus, it is difficult for us to reconcile the use of androgen supplementation in a majority of the patients included in this analysis.6,7 The stratification of outcomes based on patient age, phallus size and location of the meatus would help clarify this issue. The rate of scar formation was significantly lower in the androgen group. This finding in older boys with mild hypospadias would suggest that the true benefit of androgens may not be in the increased phallus size or improved tissue vascularity, but rather in the decreased scar formation by the androgen treated tissues. Would the rates of scar formation be improved by topical application of nonandrogen steroids? The use of human chorionic gonadotropin and androgens in the management of cryptorchidism and hypospadias provides evidence that hormonal manipulation is often clinically well tolerated. Less information is available regarding the long-term effects of such treatment in prepubertal boys, although experimental studies indicate that prepubertal human chorionic gonadotropin administration may decrease androgen production and germ cell counts in postpubertal rats.8 Although dihydrotestosterone is an end product of the androgen pathway, data exist that DHT alone can promote spermatogenesis, and the effects of such stimulation in a prepubertal boy must be carefully considered.9 We have used preoperative supplemental androgens in our patients with hypospadias based on the subjective improvement in outcomes. Considering the currently available literature, it is difficult to determine if this benefit would be justified in the face of later consequences. We believe that, similar to this study by Kaya et al, continued investigation into the use of supplemental hormones in patients with hypospadias and the long-term effects of such therapy is direly needed. Respectfully, Christopher Charles Roth, Dominic Frimberger and Bradley P. Kropp Department of Urology Children’s Hospital of Oklahoma University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma Reply by Authors. We appreciate the comments clarifying the issue about testosterone therapy in hypospadias surgery. As we know, the effect of testosterone on penile growth and the prepuce up to the day of surgery was significant in the correction of severe cases of hypospadias.6 Even in distal hypospadias cases the repair is associated with a number of complications, including urethrocutaneous fistula, stenosis and scar formation. What concerns us primarily with andro-
LETTERS TO THE EDITOR gen supplementation is improving the overall outcome after hypospadias repair, regardless of disease severity. Since we did not select any special cases (severe or not) in this series, we were able to enlarge the study group and to document the cosmetic results in common conditions such as distal hypospadias. It is true that stratification of outcomes based on age, phallus configuration (especially glans size) and location of the meatus may result in select patients benefiting most of all with DHT pretreatment. Nevertheless, since one of the reasons for dissatisfaction with the results of hypospadias surgery has been penile scars such as skin tags, skin bridges and keloid scar formation,10 our expected benefit in this study was most notably to improve the cosmetic outcome. Significantly less scar formation was found in the patient group receiving DHT pretreatment, as expressed in the article. Since this is the first known study to compare surgical outcomes in patients with and without preoperative local hormone stimulation, we chose a 3-month treatment period, similar to Charmandari et al.11 Although the ideal age for hypospadias surgery is before 2 years, not only for psychological reasons but also with respect to complication rates,12 our patient collective originated from a rural population, explaining the higher average age. We acknowledge the remarks concerning possible pathological changes of genital skin morphology. To our knowledge dermal cells increase their production of mitogenic factors in response to androgens but evolve no pathological changes or alterations in enzyme levels, eg due to treatment with androgenic alopecia cell media in vitro.13 Hypothetically, it seems possible to impact postoperative abnormal scar formation by applying nonandrogenic steroids. Although multiple factors are involved in abnormal scar formation, local steroid therapy can only be administered as soon a problem scar is identified—it is not accepted in a pretreatment regimen. It is true that prepubertal human chorionic gonadotropin administration may harm germ cell maturation. Conversely, it has been demonstrated that neoadjuvant gonadotropin-releasing hormone treatment improves the fertility index in prepubertal cryptorchidism.14 Furthermore, it has been shown that DHT provides high local concentrations at the site of application, and serum concentration remains within the normal range, although the exact dose of the application is not accurately assignable.11 We agree that various parts of the tubularized incised plate Snodgrass procedure are not exactly new. However, it is to the credit of Snodgrass to disseminate a simple and reproducible surgical technique that has achieved widespread popularity.15 1. 2. 3. 4. 5.
6.
Orkiszewski M: Dihydrotestosterone (DHT) local stimulation in hypospadias surgery. J Androl, suppl., 1985; 6: 107. Monfort G and Lucas C: Dehydrotestosterone penile stimulation in hypospadias surgery. Eur Urol 1982; 8: 201. Snodgrass W: Tubularized, incised plate urethroplasty for distal hypospadias. J Urol 1994; 151: 464. Orkiszewski M: Urethral reconstruction in skin deficit. Pol Urol 1987; 40: 12. Orkiszewski M: A longitudinal split-thickness incision to widen the Byars skin flaps as alternative to extragenital skin graft in hypospadias surgery. Presented at 15th Joint Session of the Austrian Society of Urology and Bavarian Urological Association, Vienna, June 1–3, 1989. Koff SA and Jayanthi VR: Preoperative treatment with human chorionic gonadotropin in infancy decreases the severity of proximal hypospadias and chordee. J Urol 1999; 162: 1435.
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Chalapathi G, Rao KL, Chowdhary SK, Narasimhan KL, Samujh R and Mahajan JK: Testosterone therapy in microphallic hypospadias: topical or parenteral? J Pediatr Surg 2003; 38: 221. Chandrasekharam VV, Srinivas M, Das SN, Jha P, Bajpai M, Chaki SP et al: Prepubertal human chorionic gonadotropin injection affects postpubertal germ cell maturation and androgen production in rat testis. Urology 2003; 62: 571. Chen H, Chandrashekar V and Zirkin BR: Can spermatogenesis be maintained quantitatively in intact adult rats with exogenously administered dihydrotestosterone? J Androl 1994; 15: 132. Mureau MA, Slijper FM, Nijman RJ, van der Meulen JC, Verhulst FC and Slob AK: Psychosexual adjustment of children and adolescents after different types of hypospadias surgery: a norm-related study. J Urol 1995; 154: 1902. Charmandari E, Dattani MT, Perry LA, Hindmarsh PC and Brook CG: Kinetics and effect of percutaneous administration of dihydrotestosterone in children. Horm Res 2001; 56: 177. Dodson JL, Baird AD, Baker LA, Docimo SG and Mathews RI: Outcomes of delayed hypospadias repair: implications for decision making. J Urol 2007; 178: 278. Hamada K and Randall VA: Inhibitory autocrine factors produced by the mesenchyme-derived hair follicle dermal papilla may be a key to male pattern baldness. Br J Dermatol 2006; 154: 609. Schwentner C, Oswald J, Kreczy A, Lunacek A, Bartsch G, Deibl M et al: Neoadjuvant gonadotropin-releasing hormone therapy before surgery may improve the fertility index in undescended testes: a prospective randomized trial. J Urol 2005; 173: 974. Snodgrass WT and Nguyen MT: Current technique of tubularized incised plate hypospadias repair. Urology 2002; 60: 157.
Re: Relationship Between Lower Urinary Tract Symptoms and Erectile Dysfunction: Results From the Boston Area Community Health Survey S. T. Brookes, C. L. Link, J. L. Donovan and J. B. McKinlay J Urol 2008; 179: 250 –255. To the Editor. This study is another example of those in which the relationship between lower urinary tract symptoms (LUTS) and erectile dysfunction have been examined and questionnaires have been used. In our opinion this article is far from being original because, as the authors indicate, this relationship has been shown by several other studies from different countries, using almost the same assessment tools, the International Index of Erectile Function (IIEF) and the International Prostate Symptom Score. As a different approach, these authors also investigated the impact of incontinence and prostatitis symptoms, and painful bladder syndrome on the prevalence of erectile dysfunction in a racially and ethnically diverse random sample of men. We believe that some methodological mistakes must be addressed. The collection of data seems inappropriate because these questionnaires were completed by a bilingual interviewer during a 2-hour interview, an approach that may cause bias on the part of the interviewer. As the authors mention, data regarding the IIEF-5 score were missing in about 20% of
Re: The Efficacy of Dihydrotestosterone Transdermal Gel Before Primary Hypospadias Surgery: A Prospective, Controlled, Randomized Study C. Kaya, J. Bektic, C. Radmayr, C. Schwentner, G. Bartsch and J. Oswald J Urol 2008; 179: 684 – 688. To the Editor. I read this article with interest. However, in the purpose section of the abstract I could not find the benefit expected for patients to use one of the most potent androgens known. In the materials and methods section of the article the authors state they used dihydrotestosterone (DHT) in primary repair in mainly distal hypospadias forms. It seems difficult to further improve results that are usually reported by most authors today as excellent. In our own series of patients treated with DHT the agent was only applied in highly selected multiple redo procedures (sometimes up to 15 procedures) when no genital skin was available for urethral repair, extensive scarring was found, and known surgical techniques were limited in number and choice.1 We try to avoid hypospadias surgery in patients 2 to 4 years old, as advised by psychologists, to prevent potential psychological trauma. The patients included in this study were just within this vulnerable age range. Is it possible that by using DHT we unintentionally increase aggressiveness, as is the case in sports? Originally, the recommended usage of DHT, as described by Monfort and Lucas,2 was for a duration of 4 to 5 weeks preoperatively. I also observed the expected effect of softening the skin, as per their experience. Kaya et al did not explain why they increased the doses of DHT. Neither did they report levels of DHT in the blood. In 1985 I reported the effects of DHT local stimulation in hypospadias repair on genital skin morphology.1 It showed enormous mitotic activity, which may resemble a basal cell carcinoma pattern of the skin. These changes, although time limited, resulted in my total withdrawal of DHT from the hypospadias surgery armamentarium. Dihydrotestosterone has not been approved for treatment in Poland, as is the case in many European countries. Last but not least, the authors state that the tubularized incised plate procedure was first described in 1994 by Snodgrass,3 which is incorrect. In fact, it was described by me on several occasions 7 years earlier.4,5 Respectfully, Marek Orkiszewski Department of Pediatric Surgery and Traumatology Regional Children’s Hospital Collegium Medicum Nicolaus Copernicus University Torun, Poland To the Editor. Kaya et al deserve commendation for their contribution to the medical literature regarding the role of supplemental androgens in the management of hypospadias. The current study represents a significant link between what, in our opinion, is a relatively common practice of androgen supplementation and the evidence that such
therapy actually improves outcomes. While it has been suggested for the last 3 decades that androgen supplementation will decrease complications, the authors describe the only well designed, prospective study in the current literature to support this claim. One considerable area where this study failed to advance our understanding of hypospadias repair is in the selection of patients most likely to benefit from hormonal supplementation. The mean age of the patients enrolled in the study was nearly 3 years, with boys up to 13 years being included in the evaluation. It is noteworthy that most of the patients had mild hypospadias, with 77% having a coronal location of the meatus. Based on the previous literature, which supports the use of hormonal stimulation in proximal hypospadias and microphallus, it is difficult for us to reconcile the use of androgen supplementation in a majority of the patients included in this analysis.6,7 The stratification of outcomes based on patient age, phallus size and location of the meatus would help clarify this issue. The rate of scar formation was significantly lower in the androgen group. This finding in older boys with mild hypospadias would suggest that the true benefit of androgens may not be in the increased phallus size or improved tissue vascularity, but rather in the decreased scar formation by the androgen treated tissues. Would the rates of scar formation be improved by topical application of nonandrogen steroids? The use of human chorionic gonadotropin and androgens in the management of cryptorchidism and hypospadias provides evidence that hormonal manipulation is often clinically well tolerated. Less information is available regarding the long-term effects of such treatment in prepubertal boys, although experimental studies indicate that prepubertal human chorionic gonadotropin administration may decrease androgen production and germ cell counts in postpubertal rats.8 Although dihydrotestosterone is an end product of the androgen pathway, data exist that DHT alone can promote spermatogenesis, and the effects of such stimulation in a prepubertal boy must be carefully considered.9 We have used preoperative supplemental androgens in our patients with hypospadias based on the subjective improvement in outcomes. Considering the currently available literature, it is difficult to determine if this benefit would be justified in the face of later consequences. We believe that, similar to this study by Kaya et al, continued investigation into the use of supplemental hormones in patients with hypospadias and the long-term effects of such therapy is direly needed. Respectfully, Christopher Charles Roth, Dominic Frimberger and Bradley P. Kropp Department of Urology Children’s Hospital of Oklahoma University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma Reply by Authors. We appreciate the comments clarifying the issue about testosterone therapy in hypospadias surgery. As we know, the effect of testosterone on penile growth and the prepuce up to the day of surgery was significant in the correction of severe cases of hypospadias.6 Even in distal hypospadias cases the repair is associated with a number of complications, including urethrocutaneous fistula, stenosis and scar formation. What concerns us primarily with andro-
LETTERS TO THE EDITOR gen supplementation is improving the overall outcome after hypospadias repair, regardless of disease severity. Since we did not select any special cases (severe or not) in this series, we were able to enlarge the study group and to document the cosmetic results in common conditions such as distal hypospadias. It is true that stratification of outcomes based on age, phallus configuration (especially glans size) and location of the meatus may result in select patients benefiting most of all with DHT pretreatment. Nevertheless, since one of the reasons for dissatisfaction with the results of hypospadias surgery has been penile scars such as skin tags, skin bridges and keloid scar formation,10 our expected benefit in this study was most notably to improve the cosmetic outcome. Significantly less scar formation was found in the patient group receiving DHT pretreatment, as expressed in the article. Since this is the first known study to compare surgical outcomes in patients with and without preoperative local hormone stimulation, we chose a 3-month treatment period, similar to Charmandari et al.11 Although the ideal age for hypospadias surgery is before 2 years, not only for psychological reasons but also with respect to complication rates,12 our patient collective originated from a rural population, explaining the higher average age. We acknowledge the remarks concerning possible pathological changes of genital skin morphology. To our knowledge dermal cells increase their production of mitogenic factors in response to androgens but evolve no pathological changes or alterations in enzyme levels, eg due to treatment with androgenic alopecia cell media in vitro.13 Hypothetically, it seems possible to impact postoperative abnormal scar formation by applying nonandrogenic steroids. Although multiple factors are involved in abnormal scar formation, local steroid therapy can only be administered as soon a problem scar is identified—it is not accepted in a pretreatment regimen. It is true that prepubertal human chorionic gonadotropin administration may harm germ cell maturation. Conversely, it has been demonstrated that neoadjuvant gonadotropin-releasing hormone treatment improves the fertility index in prepubertal cryptorchidism.14 Furthermore, it has been shown that DHT provides high local concentrations at the site of application, and serum concentration remains within the normal range, although the exact dose of the application is not accurately assignable.11 We agree that various parts of the tubularized incised plate Snodgrass procedure are not exactly new. However, it is to the credit of Snodgrass to disseminate a simple and reproducible surgical technique that has achieved widespread popularity.15 1. 2. 3. 4. 5.
6.
Orkiszewski M: Dihydrotestosterone (DHT) local stimulation in hypospadias surgery. J Androl, suppl., 1985; 6: 107. Monfort G and Lucas C: Dehydrotestosterone penile stimulation in hypospadias surgery. Eur Urol 1982; 8: 201. Snodgrass W: Tubularized, incised plate urethroplasty for distal hypospadias. J Urol 1994; 151: 464. Orkiszewski M: Urethral reconstruction in skin deficit. Pol Urol 1987; 40: 12. Orkiszewski M: A longitudinal split-thickness incision to widen the Byars skin flaps as alternative to extragenital skin graft in hypospadias surgery. Presented at 15th Joint Session of the Austrian Society of Urology and Bavarian Urological Association, Vienna, June 1–3, 1989. Koff SA and Jayanthi VR: Preoperative treatment with human chorionic gonadotropin in infancy decreases the severity of proximal hypospadias and chordee. J Urol 1999; 162: 1435.
7.
8.
9.
10.
11.
12.
13.
14.
15.
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Chalapathi G, Rao KL, Chowdhary SK, Narasimhan KL, Samujh R and Mahajan JK: Testosterone therapy in microphallic hypospadias: topical or parenteral? J Pediatr Surg 2003; 38: 221. Chandrasekharam VV, Srinivas M, Das SN, Jha P, Bajpai M, Chaki SP et al: Prepubertal human chorionic gonadotropin injection affects postpubertal germ cell maturation and androgen production in rat testis. Urology 2003; 62: 571. Chen H, Chandrashekar V and Zirkin BR: Can spermatogenesis be maintained quantitatively in intact adult rats with exogenously administered dihydrotestosterone? J Androl 1994; 15: 132. Mureau MA, Slijper FM, Nijman RJ, van der Meulen JC, Verhulst FC and Slob AK: Psychosexual adjustment of children and adolescents after different types of hypospadias surgery: a norm-related study. J Urol 1995; 154: 1902. Charmandari E, Dattani MT, Perry LA, Hindmarsh PC and Brook CG: Kinetics and effect of percutaneous administration of dihydrotestosterone in children. Horm Res 2001; 56: 177. Dodson JL, Baird AD, Baker LA, Docimo SG and Mathews RI: Outcomes of delayed hypospadias repair: implications for decision making. J Urol 2007; 178: 278. Hamada K and Randall VA: Inhibitory autocrine factors produced by the mesenchyme-derived hair follicle dermal papilla may be a key to male pattern baldness. Br J Dermatol 2006; 154: 609. Schwentner C, Oswald J, Kreczy A, Lunacek A, Bartsch G, Deibl M et al: Neoadjuvant gonadotropin-releasing hormone therapy before surgery may improve the fertility index in undescended testes: a prospective randomized trial. J Urol 2005; 173: 974. Snodgrass WT and Nguyen MT: Current technique of tubularized incised plate hypospadias repair. Urology 2002; 60: 157.
Re: Relationship Between Lower Urinary Tract Symptoms and Erectile Dysfunction: Results From the Boston Area Community Health Survey S. T. Brookes, C. L. Link, J. L. Donovan and J. B. McKinlay J Urol 2008; 179: 250 –255. To the Editor. This study is another example of those in which the relationship between lower urinary tract symptoms (LUTS) and erectile dysfunction have been examined and questionnaires have been used. In our opinion this article is far from being original because, as the authors indicate, this relationship has been shown by several other studies from different countries, using almost the same assessment tools, the International Index of Erectile Function (IIEF) and the International Prostate Symptom Score. As a different approach, these authors also investigated the impact of incontinence and prostatitis symptoms, and painful bladder syndrome on the prevalence of erectile dysfunction in a racially and ethnically diverse random sample of men. We believe that some methodological mistakes must be addressed. The collection of data seems inappropriate because these questionnaires were completed by a bilingual interviewer during a 2-hour interview, an approach that may cause bias on the part of the interviewer. As the authors mention, data regarding the IIEF-5 score were missing in about 20% of