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The Changing Elaboration of Inhibin B in Patients with Unilateral Testicular Maldescent vs Vanished Testis
The Changing Elaboration of Inhibin B in Patients with Unilateral Testicular Maldescent vs Vanished Testis ONE of the most difficult and frustrating aspects of dealing with testicular problems in children is the uncertainty surrounding subsequent androgen production and the ultimate ability to father biological offspring. Questions around this issue cause a lot of parental anxiety and are the driving force behind interventions such as orchiopexy, aimed at minimizing the possibility of future problems. Even then, doubt lingers. Having a way to risk stratify patients early in life, without doing a testicular biopsy,1 would be a welcome addition to our armamentarium. We are in dire need of a simple, reliable serum marker! Enter inhibin B, a molecule produced and secreted by testicular Sertoli cells that has a key role in regulating pituitary follicle-stimulating hormone secretion and synthesis. Low inhibin B levels are associated with a significant increase in follicle-stimulating hormone secretion.2 This association has triggered research into a diagnostic or predictive role in disorders of spermatogenesis. Low inhibin B levels have been detected in men with a history of cryptorchidism (compared to normal controls),3 likely reflecting irreversible damage to the cryptorchid testis before or despite surgery. Serum inhibin B levels in childhood are decreased in cryptorchid males younger than 4 years,4 suggesting that this hormone could be used as a marker to predict spermatogenesis and potential future fertility.5 Although the level and amount of evidence are modest, things are looking promising for this test. Adding to the available evidence, in this issue of The Journal Thorup et al (page 1632) provide further analyses of their rich database,6 now exploring the hypothesis that serum inhibin B levels in boys with a unilateral vanished testis increase as a result of contralateral testicular hypertrophy, a phenomenon thought to occur in these children based on measurement studies done on the normal descended solitary gonad.7,8 Their assumption is corroborated by previous data demonstrating a positive correlation between testicular volume and levels of inhibin B.9 In the study by Thorup et al
0022-5347/15/1935-1465/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
only 5% of boys 6 to 18 months old vs 67% of those 18 to 60 months old had inhibin B levels above normal.6 Accordingly the authors propose that this difference is due to an increase in the number of Sertoli and/or germ cells, representing indirect evidence of development of testicular hypertrophy or hyperplasia. Unfortunately a reasonable hypothesis and a possible association are hardly enough to support causality between the proposed stimulus (changes in testicular germinal epithelium) and outcome (increase in inhibin B levels). These authors have also postulated that development of contralateral testicular hypertrophy with normalization of inhibin B levels should be expected to occur between ages 1 and 2 years. Contralateral testicular hypertrophy has been observed in boys with monorchidism as early as age 9 months.7 Unfortunately testicular volume measurements in patients with vanished testes at different age points were not available in the present study to support their hypothesis, information that appears critical to help us understand the connection between inhibin B and germinal epithelium or Sertoli cell aggregate mass. The results of Thorup et al show that there was no significant difference between the number of boys with cryptorchidism and inhibin B levels above normal (24%) and those with a vanished testis (17%), indicating that serum inhibin B values may be a useful parameter to reflect the state of germinative epithelium in cryptorchid testes.6 However, increases in inhibin B levels are neither an accurate nor a practical way to diagnose vanished testes. Although interesting, it is hard to find conclusive helpful cutoffs around the values (due to expected fluctuations and measurement errors). Similarly inhibin B levels are still far from giving us information that would discriminate between groups or monitor useful trends for patients through time, lacking good correlation from a clinical perspective. Conversely simple observations from clinical practice have revealed that increase in size (length and volume) of the contralateral testis in boys with a unilateral vanished testis is a better and reliable
http://dx.doi.org/10.1016/j.juro.2015.02.076 Vol. 193, 1465-1466, May 2015 Printed in U.S.A.
www.jurology.com
j
1465
1466
INHIBIN B IN PATIENTS WITH TESTICULAR MALDESCENT VS VANISHED TESTIS
predictor of monorchidism.7,8 Furthermore, palpation of a testicular nubbin with the child under anesthesia before orchiopexy is a convenient way to confirm the diagnosis of vanished testis and inform the surgical approach.10 Having 2 normally descended testicles is not a guarantee of fertility, and cryptorchidism (particularly unilateral) or monorchidism is far from a sentence to experience infertility or subfertility.11 At the end of the day the question is whether one should draw blood from an infant who has been scheduled for orchiopexy to counsel families about fertility potential or diagnose vanished testis. The answer is probably not. Based on the current evidence, measuring inhibin B levels in patients
undergoing orchiopexy may be better limited to research protocols, allowing clinical judgment and intuition based on practical observations to guide surgical decisions regarding vanished testes. Luis H. Braga Department of Surgery/Urology McMaster Children’s Hospital McMaster University Hamilton
and Armando J. Lorenzo Department of Surgery/Urology Hospital for Sick Children University of Toronto Toronto Ontario, Canada
REFERENCES 1. Thorup J, Kvist K, Clasen-Linde E et al: The relation between adult dark spermatogonia and other parameters of fertility potential in cryptorchid testes. J Urol, suppl., 2013; 190: 1566.
5. Kumanov P, Nandipati K, Tomova A et al: Inhibin B is a better marker of spermatogenesis than other hormones in the evaluation of male factor infertility. Fertil Steril 2006; 86: 332.
2. Anderson RA and Sharpe RM: Regulation of inhibin production in the human male and its clinical applications. Int J Androl 2000; 23: 136.
6. Thorup J, Kvist K, Clasen-Linde E et al: Serum inhibin B values in boys with unilateral vanished testis or unilateral cryptorchidism. J Urol 2015; 193: 1632.
3. Lee PA, Coughlin MT and Bellinger MF: Inhibin B: comparison with indexes of fertility among formerly cryptorchid and control men. J Clin Endocrinol Metab 2001; 86: 2576. 4. Longui CA, Arnhold IJ, Mendonca BB et al: Serum inhibin levels before and after gonadotropin stimulation in cryptorchid boys under age 4 years. J Pediatr Endocrinol Metab 1998; 11: 687.
7. Braga LH, Kim S, Farrokhyar F et al: Is there an optimal contralateral testicular cut-off size that predicts monorchism in boys with nonpalpable testicles? J Pediatr Urol 2014; 10: 693. 8. Shibata Y, Kojima Y, Mizuno K et al: Optimal cutoff value of contralateral testicular size for prediction of absent testis in Japanese boys with nonpalpable testis. Urology 2010; 76: 78.
9. Kollin C, Stukenborg JB, Nurmio M et al: Boys with undescended testes: endocrine, volumetric and morphometric studies on testicular function before and after orchidopexy at nine months or three years of age. J Clin Endocrinol Metab 2012; 97: 4588.
10. Snodgrass WT, Yucel S and Ziada A: Scrotal exploration for unilateral nonpalpable testis. J Urol 2007; 178: 1718.
11. Lee PA and Coughlin MT: The single testis: paternity after presentation as unilateral cryptorchidism. J Urol 2002; 168: 1680.
0022-5347/15/1935-1465/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
only 5% of boys 6 to 18 months old vs 67% of those 18 to 60 months old had inhibin B levels above normal.6 Accordingly the authors propose that this difference is due to an increase in the number of Sertoli and/or germ cells, representing indirect evidence of development of testicular hypertrophy or hyperplasia. Unfortunately a reasonable hypothesis and a possible association are hardly enough to support causality between the proposed stimulus (changes in testicular germinal epithelium) and outcome (increase in inhibin B levels). These authors have also postulated that development of contralateral testicular hypertrophy with normalization of inhibin B levels should be expected to occur between ages 1 and 2 years. Contralateral testicular hypertrophy has been observed in boys with monorchidism as early as age 9 months.7 Unfortunately testicular volume measurements in patients with vanished testes at different age points were not available in the present study to support their hypothesis, information that appears critical to help us understand the connection between inhibin B and germinal epithelium or Sertoli cell aggregate mass. The results of Thorup et al show that there was no significant difference between the number of boys with cryptorchidism and inhibin B levels above normal (24%) and those with a vanished testis (17%), indicating that serum inhibin B values may be a useful parameter to reflect the state of germinative epithelium in cryptorchid testes.6 However, increases in inhibin B levels are neither an accurate nor a practical way to diagnose vanished testes. Although interesting, it is hard to find conclusive helpful cutoffs around the values (due to expected fluctuations and measurement errors). Similarly inhibin B levels are still far from giving us information that would discriminate between groups or monitor useful trends for patients through time, lacking good correlation from a clinical perspective. Conversely simple observations from clinical practice have revealed that increase in size (length and volume) of the contralateral testis in boys with a unilateral vanished testis is a better and reliable
http://dx.doi.org/10.1016/j.juro.2015.02.076 Vol. 193, 1465-1466, May 2015 Printed in U.S.A.
www.jurology.com
j
1465
1466
INHIBIN B IN PATIENTS WITH TESTICULAR MALDESCENT VS VANISHED TESTIS
predictor of monorchidism.7,8 Furthermore, palpation of a testicular nubbin with the child under anesthesia before orchiopexy is a convenient way to confirm the diagnosis of vanished testis and inform the surgical approach.10 Having 2 normally descended testicles is not a guarantee of fertility, and cryptorchidism (particularly unilateral) or monorchidism is far from a sentence to experience infertility or subfertility.11 At the end of the day the question is whether one should draw blood from an infant who has been scheduled for orchiopexy to counsel families about fertility potential or diagnose vanished testis. The answer is probably not. Based on the current evidence, measuring inhibin B levels in patients
undergoing orchiopexy may be better limited to research protocols, allowing clinical judgment and intuition based on practical observations to guide surgical decisions regarding vanished testes. Luis H. Braga Department of Surgery/Urology McMaster Children’s Hospital McMaster University Hamilton
and Armando J. Lorenzo Department of Surgery/Urology Hospital for Sick Children University of Toronto Toronto Ontario, Canada
REFERENCES 1. Thorup J, Kvist K, Clasen-Linde E et al: The relation between adult dark spermatogonia and other parameters of fertility potential in cryptorchid testes. J Urol, suppl., 2013; 190: 1566.
5. Kumanov P, Nandipati K, Tomova A et al: Inhibin B is a better marker of spermatogenesis than other hormones in the evaluation of male factor infertility. Fertil Steril 2006; 86: 332.
2. Anderson RA and Sharpe RM: Regulation of inhibin production in the human male and its clinical applications. Int J Androl 2000; 23: 136.
6. Thorup J, Kvist K, Clasen-Linde E et al: Serum inhibin B values in boys with unilateral vanished testis or unilateral cryptorchidism. J Urol 2015; 193: 1632.
3. Lee PA, Coughlin MT and Bellinger MF: Inhibin B: comparison with indexes of fertility among formerly cryptorchid and control men. J Clin Endocrinol Metab 2001; 86: 2576. 4. Longui CA, Arnhold IJ, Mendonca BB et al: Serum inhibin levels before and after gonadotropin stimulation in cryptorchid boys under age 4 years. J Pediatr Endocrinol Metab 1998; 11: 687.
7. Braga LH, Kim S, Farrokhyar F et al: Is there an optimal contralateral testicular cut-off size that predicts monorchism in boys with nonpalpable testicles? J Pediatr Urol 2014; 10: 693. 8. Shibata Y, Kojima Y, Mizuno K et al: Optimal cutoff value of contralateral testicular size for prediction of absent testis in Japanese boys with nonpalpable testis. Urology 2010; 76: 78.
9. Kollin C, Stukenborg JB, Nurmio M et al: Boys with undescended testes: endocrine, volumetric and morphometric studies on testicular function before and after orchidopexy at nine months or three years of age. J Clin Endocrinol Metab 2012; 97: 4588.
10. Snodgrass WT, Yucel S and Ziada A: Scrotal exploration for unilateral nonpalpable testis. J Urol 2007; 178: 1718.
11. Lee PA and Coughlin MT: The single testis: paternity after presentation as unilateral cryptorchidism. J Urol 2002; 168: 1680.