Download PDF
Eur J Pediatr Surg 2016; 26(05): 409-417
DOI: 10.1055/s-0036-1592415
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Hormonal Aspects of the Pathogenesis and Treatment of Cryptorchidism

Dina Cortes
1   Department of Pediatrics, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
2   Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
,
Rune Holt
1   Department of Pediatrics, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
,
Victoria Elizabeth de Knegt
1   Department of Pediatrics, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
› Author Affiliations
Further Information

Publication History

22 July 2016

09 August 2016

Publication Date:
19 September 2016 (online)

    Permissions and Reprints

Abstract

A normal functioning hypothalamic–pituitary–testicular axis is required for normal testicular descent. The percentage of cases that result from a disturbance in this axis remains controversial. Much has yet to be learnt about cryptorchidism, but is seems that the existence of A dark spermatogonia (Ad spermatogonia) is essential for later fertility. Bilateral cryptorchid patients have a high risk of later infertility, even though they undergo early surgery for cryptorchidism. It is possible today to distinguish—to a certain extent—between three different groups of cryptorchid patients based on testicular histology, gonadotropins, and inhibin B at the time of early surgery: Group 1, patients suspected of prepubertal transient hypothalamic–pituitary–testicular hypofunction and a high risk of later infertility; Group 2, patients with hypergonadotropic hypogonadism and a primary testicular dysfunction; and Group 3, patients with normal histology and normal serum levels of inhibin B and gonadotropins at the time of early surgery and a low risk of later infertility. Given the potential adverse effects of hormonal treatment, attention should be directed toward small doses of adjuvant gonadotropin-releasing hormone (GnRH) treatment for those who might benefit the most, that is, bilateral cryptorchid boys at early surgery without evidence of normal maturation of gonocytes into Ad spermatogonia. Optimally, gonadotropin levels in such patients should be measured to ensure that levels are not compensatory elevated, thereby supporting the suspicion of hypothalamic–pituitary–testicular hypofunction. Studies of GnRH-supplementary treatment should include testicular biopsy at surgery and at follow-up in childhood as well as examinations of fertility potential in adulthood.

Keywords

cryptorchidism - testis - hormone - treatment - pathogenesis
 

  • References

  • 1 Trsinar B, Muravec UR. Fertility potential after unilateral and bilateral orchidopexy for cryptorchidism. World J Urol 2009; 27 (4) 513-519
    CrossrefPubMedGoogle Scholar
  • 2 Cortes D, Thorup JM, Visfeldt J. Cryptorchidism: aspects of fertility and neoplasms. A study including data of 1,335 consecutive boys who underwent testicular biopsy simultaneously with surgery for cryptorchidism. Horm Res 2001; 55 (1) 21-27
    CrossrefPubMedGoogle Scholar
  • 3 Cortes D, Thorup JM, Beck BL. Quantitative histology of germ cells in the undescended testes of human fetuses, neonates and infants. J Urol 1995; 154 (3) 1188-1192
    CrossrefPubMedGoogle Scholar
  • 4 Hadziselimovic F, Herzog B. The importance of both an early orchidopexy and germ cell maturation for fertility. Lancet 2001; 358 (9288) 1156-1157
    CrossrefPubMedGoogle Scholar
  • 5 Hadziselimovic F, Hoecht B. Testicular histology related to fertility outcome and postpubertal hormone status in cryptorchidism. Klin Padiatr 2008; 220 (5) 302-307
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Lala R, Matarazzo P, Chiabotto P, de Sanctis C, Canavese F, Hadziselimovic F. Combined therapy with LHRH and HCG in cryptorchid infants. Eur J Pediatr 1993; 152 (Suppl. 02) S31-S33
    CrossrefPubMedGoogle Scholar
  • 7 Lala R, Matarazzo P, Chiabotto P , et al. Early hormonal and surgical treatment of cryptorchidism. J Urol 1997; 157 (5) 1898-1901
    CrossrefPubMedGoogle Scholar
  • 8 Ritzén EM, Bergh A, Bjerknes R , et al. Nordic consensus on treatment of undescended testes. Acta Paediatr 2007; 96 (5) 638-643
    CrossrefPubMedGoogle Scholar
  • 9 Kolon TF, Herndon CDA, Baker LA , et al; American Urological Assocation. Evaluation and treatment of cryptorchidism: AUA guideline. J Urol 2014; 192 (2) 337-345
    CrossrefPubMedGoogle Scholar
  • 10 Tekgül S, Dogan HS, Hoebeke P , et al. ESPU, European Society for Paediatric Urology. Undescended testes. Available at: http://uroweb.org/guideline/paediatric-urology/ . Accessed 2016
    PubMedGoogle Scholar
  • 11 Thorup J, Petersen BL, Kvist K, Cortes D. Bilateral undescended testes classified according to preoperative and postoperative status of gonadotropins and inhibin B in relation to testicular histopathology at bilateral orchiopexy in infant boys. J Urol 2012; 188 (4, Suppl): 1436-1442
    CrossrefPubMedGoogle Scholar
  • 12 Kuiri-Hänninen T, Sankilampi U, Dunkel L. Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty. Horm Res Paediatr 2014; 82 (2) 73-80
    CrossrefPubMedGoogle Scholar
  • 13 Barthold JS. What regulates neonatal gonocyte migration?. J Urol 2015; 193 (4) 1087-1088
    CrossrefPubMedGoogle Scholar
  • 14 Hutson JM, Thorup JM, Beasley SW. Descent of the Testis, 2nd ed. Switzerland: Springer International Publishing AG; 2016: 54-158
    CrossrefGoogle Scholar
  • 15 Kuiri-Hänninen T, Seuri R, Tyrväinen E , et al. Increased activity of the hypothalamic-pituitary-testicular axis in infancy results in increased androgen action in premature boys. J Clin Endocrinol Metab 2011; 96 (1) 98-105
    CrossrefPubMedGoogle Scholar
  • 16 Boukari K, Meduri G, Brailly-Tabard S , et al. Lack of androgen receptor expression in Sertoli cells accounts for the absence of anti-Mullerian hormone repression during early human testis development. J Clin Endocrinol Metab 2009; 94 (5) 1818-1825
    CrossrefPubMedGoogle Scholar
  • 17 Aksglaede L, Sørensen K, Boas M , et al. Changes in anti-Müllerian hormone (AMH) throughout the life span: a population-based study of 1027 healthy males from birth (cord blood) to the age of 69 years. J Clin Endocrinol Metab 2010; 95 (12) 5357-5364
    CrossrefPubMedGoogle Scholar
  • 18 Andersson AM, Toppari J, Haavisto AM , et al. Longitudinal reproductive hormone profiles in infants: peak of inhibin B levels in infant boys exceeds levels in adult men. J Clin Endocrinol Metab 1998; 83 (2) 675-681
    CrossrefPubMedGoogle Scholar
  • 19 Hadziselimovic F, Huff D. Gonadal differentiation—normal and abnormal testicular development. Adv Exp Med Biol 2002; 511: 15-21 , discussion 21–23
    PubMedGoogle Scholar
  • 20 Manku G, Culty M. Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges. Reproduction 2015; 149 (3) R139-R157
    CrossrefPubMedGoogle Scholar
  • 21 Hadziselimovic F. Successful treatment of unilateral cryptorchid boys risking infertility with LH-RH analogue. Int Braz J Urol 2008; 34 (3) 319-326 , discussion 327–328
    CrossrefPubMedGoogle Scholar
  • 22 Zivkovic D, Bica DT, Hadziselimovic F. Relationship between adult dark spermatogonia and secretory capacity of Leydig cells in cryptorchidism. BJU Int 2007; 100 (5) 1147-1149 , discussion 1149
    PubMedGoogle Scholar
  • 23 Su S, Szarek M, Vooght A, Hutson J, Li R. Gonocyte transformation to spermatogonial stem cells occurs earlier in patients with undervirilisation syndromes. J Pediatr Surg 2014; 49 (2) 323-327
    CrossrefPubMedGoogle Scholar
  • 24 Verkauskas G, Malcius D, Eidukaite A , et al. Prospective study of histological and endocrine parameters of gonadal function in boys with cryptorchidism. J Pediatr Urol 2016; 12 (4) 239.e1-6
    PubMedGoogle Scholar
  • 25 Li R, Thorup J, Sun C, Cortes D, Southwell B, Hutson J. Immunofluorescent analysis of testicular biopsies with germ cell and Sertoli cell markers shows significant MVH negative germ cell depletion with older age at orchiopexy. J Urol 2014; 191 (2) 458-464
    CrossrefPubMedGoogle Scholar
  • 26 Li R, Vannitamby A, Meijer J, Southwell B, Hutson J. Postnatal germ cell development during mini-puberty in the mouse does not require androgen receptor: implications for managing cryptorchidism. J Urol 2015; 193 (4) 1361-1367
    CrossrefPubMedGoogle Scholar
  • 27 Miles DC, Wakeling SI, Stringer JM , et al. Signaling through the TGF beta-activin receptors ALK4/5/7 regulates testis formation and male germ cell development. PLoS ONE 2013; 8 (1) e54606
    CrossrefPubMedGoogle Scholar
  • 28 Cortes D, Clasen-Linde E, Hutson JM, Li R, Thorup J. The Sertoli cell hormones inhibin-B and anti Müllerian hormone have different patterns of secretion in prepubertal cryptorchid boys. J Pediatr Surg 2016; 51 (3) 475-480
    CrossrefPubMedGoogle Scholar
  • 29 Cortes D, Visfeldt J, Thorup JM. Erythropoietin may reduce the risk of germ cell loss in boys with cryptorchidism. Horm Res 2001; 55 (1) 41-45
    CrossrefPubMedGoogle Scholar
  • 30 Gendrel D, Roger M, Job JC. Plasma gonadotropin and testosterone values in infants with cryptorchidism. J Pediatr 1980; 97 (2) 217-220
    CrossrefPubMedGoogle Scholar
  • 31 Barthold JS, Manson J, Regan V , et al. Reproductive hormone levels in infants with cryptorchidism during postnatal activation of the pituitary-testicular axis. J Urol 2004; 172 (4 Pt 2) 1736-1741 , discussion 1741
    CrossrefPubMedGoogle Scholar
  • 32 Toppari J, Kaleva M, Virtanen HE, Main KM, Skakkebaek NE. Luteinizing hormone in testicular descent. Mol Cell Endocrinol 2007; 269 (1–2) 34-37
    CrossrefPubMedGoogle Scholar
  • 33 Sadov S, Koskenniemi JJ, Virtanen HE , et al. Testicular growth during puberty in boys with and without a history of congenital cryptorchidism. J Clin Endocrinol Metab 2016; 101 (6) 2570-2577
    CrossrefPubMedGoogle Scholar
  • 34 Thorup J, Clasen-Linde E, Thorup SC , et al. Pre- and postoperative status of gonadotropins (FSH and LH) and inhibin B in relation to testicular histopathology at orchidopexy in infant boys with unilateral undescended testes. J Pediatr Urol 2015; 11 (1) 25.e1-5
    CrossrefPubMedGoogle Scholar
  • 35 Cortes D, Thorup J, Lindenberg S, Visfeldt J. Infertility despite surgery for cryptorchidism in childhood can be classified by patients with normal or elevated follicle-stimulating hormone and identified at orchidopexy. BJU Int 2003; 91 (7) 670-674
    CrossrefPubMedGoogle Scholar
  • 36 Thorup J, Kvist K, Clasen-Linde E, Petersen BL, Cortes D. The relation between adult dark spermatogonia and other parameters of fertility potential in cryptorchid testes. J Urol 2013; 190 (4, Suppl): 1566-1571
    CrossrefPubMedGoogle Scholar
  • 37 Christiansen P, Andersson AM, Skakkebaek NE, Juul A. Serum inhibin B, FSH, LH and testosterone levels before and after human chorionic gonadotropin stimulation in prepubertal boys with cryptorchidism. Eur J Endocrinol 2002; 147 (1) 95-101
    CrossrefPubMedGoogle Scholar
  • 38 Kubini K, Zachmann M, Albers N , et al. Basal inhibin B and the testosterone response to human chorionic gonadotropin correlate in prepubertal boys. J Clin Endocrinol Metab 2000; 85 (1) 134-138
    CrossrefPubMedGoogle Scholar
  • 39 Irkilata HC, Yildirim I, Onguru O, Aydur E, Musabak U, Dayanc M. The influence of orchiopexy on serum inhibin B level: relationship with histology. J Urol 2004; 172 (6 Pt 1): 2402-2405 , discussion 2405
    CrossrefPubMedGoogle Scholar
  • 40 Main KM, Toppari J, Suomi AM , et al. Larger testes and higher inhibin B levels in Finnish than in Danish newborn boys. J Clin Endocrinol Metab 2006; 91 (7) 2732-2737
    CrossrefPubMedGoogle Scholar
  • 41 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 (12) 4588-4595
    CrossrefPubMedGoogle Scholar
  • 42 Thorup J, Kvist K, Clasen-Linde E, Hutson JM, Cortes D. Serum inhibin B values in boys with unilateral vanished testis or unilateral cryptorchidism. J Urol 2015; 193 (5) 1632-1636
    CrossrefPubMedGoogle Scholar
  • 43 Misra M, MacLaughlin DT, Donahoe PK, Lee MM. Measurement of Mullerian inhibiting substance facilitates management of boys with microphallus and cryptorchidism. J Clin Endocrinol Metab 2002; 87 (8) 3598-3602
    CrossrefPubMedGoogle Scholar
  • 44 Hutson JM, Li R, Vikraman J, Loebenstein M. What animal models of testicular descent and germ cell maturation tell us about the mechanism in humans. Eur J Pediatr Surg 2016; ; doi: 10.1055/s-0036-1592196.
    PubMedGoogle Scholar
  • 45 Kraft KH, Canning DA, Snyder III HM, Kolon TF. Undescended testis histology correlation with adult hormone levels and semen analysis. J Urol 2012; 188 (4, Suppl): 1429-1435
    CrossrefPubMedGoogle Scholar
  • 46 Canavese F, Mussa A, Manenti M , et al. Sperm count of young men surgically treated for cryptorchidism in the first and second year of life: fertility is better in children treated at a younger age. Eur J Pediatr Surg 2009; 19 (6) 388-391
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Cortes D. Undescended testis histology correlation with adult hormone levels and semen analysis [Editorial Comment]. J Urol 2012; 188 (4, Suppl): 1435
    CrossrefPubMedGoogle Scholar
  • 48 Kolon TF. Re. “Prospective study of histological and endocrine parameters of gonadal function in boys with cryptorchidism”. J Pediatr Urol 2016; 12: 240
    CrossrefPubMedGoogle Scholar
  • 49 Miller OF, Stock JA, Cilento BG, McAleer IM, Kaplan GW. Prospective evaluation of human chorionic gonadotropin in the differentiation of undescended testes from retractile testes. J Urol 2003; 169 (6) 2328-2331
    CrossrefPubMedGoogle Scholar
  • 50 Bu Q, Pan Z, Jiang S, Wang A, Cheng H. The effectiveness of hCG and LHRH in boys with cryptorchidism: a meta-analysis of randomized controlled trials. Horm Metab Res 2016; 48 (5) 318-324
    Article in Thieme ConnectPubMedGoogle Scholar
  • 51 Chua ME, Mendoza JS, Gaston MJV, Luna Jr SL, Morales Jr ML. Hormonal therapy using gonadotropin releasing hormone for improvement of fertility index among children with cryptorchidism: a meta-analysis and systematic review. J Pediatr Surg 2014; 49 (11) 1659-1667
    CrossrefPubMedGoogle Scholar
  • 52 Feyles F, Peiretti V, Mussa A , et al. Improved sperm count and motility in young men surgically treated for cryptorchidism in the first year of life. Eur J Pediatr Surg 2014; 24 (5) 376-380
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Cortes D, Thorup J, Visfeldt J. Hormonal treatment may harm the germ cells in 1 to 3-year-old boys with cryptorchidism. J Urol 2000; 163 (4) 1290-1292
    CrossrefPubMedGoogle Scholar
  • 54 Schwentner C, Oswald J, Kreczy A , 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 (3) 974-977
    CrossrefPubMedGoogle Scholar
  • 55 Jallouli M, Rebai T, Abid N, Bendhaou M, Kassis M, Mhiri R. Neoadjuvant gonadotropin-releasing hormone therapy before surgery and effect on fertility index in unilateral undescended testes: a prospective randomized trial. Urology 2009; 73 (6) 1251-1254
    CrossrefPubMedGoogle Scholar
  • 56 Hjertkvist M, Läckgren G, Plöen L, Bergh A. Does HCG treatment induce inflammation-like changes in undescended testes in boys?. J Pediatr Surg 1993; 28 (2) 254-258
    CrossrefPubMedGoogle Scholar
  • 57 Heiskanen P, Billig H, Toppari J , et al. Apoptotic cell death in the normal and cryptorchid human testis: the effect of human chorionic gonadotropin on testicular cell survival. Pediatr Res 1996; 40 (2) 351-356
    CrossrefPubMedGoogle Scholar
  • 58 Dunkel L, Taskinen S, Hovatta O, Tilly JL, Wikström S. Germ cell apoptosis after treatment of cryptorchidism with human chorionic gonadotropin is associated with impaired reproductive function in the adult. J Clin Invest 1997; 100 (9) 2341-2346
    CrossrefPubMedGoogle Scholar
  • 59 Varela-Cives R, Méndez-Gallart R, Estevez-Martinez E , et al. A cross-sectional study of cryptorchidism in children: testicular volume and hormonal function at 18 years of age. Int Braz J Urol 2015; 41 (1) 57-66
    CrossrefPubMedGoogle Scholar
  • 60 Taskinen S, Hovatta O, Wikström S. Early treatment of cryptorchidism, semen quality and testicular endocrinology. J Urol 1996; 156 (1) 82-84
    CrossrefPubMedGoogle Scholar
  • 61 Vinardi S, Magro P, Manenti M , et al. Testicular function in men treated in childhood for undescended testes. J Pediatr Surg 2001; 36 (2) 385-388
    CrossrefPubMedGoogle Scholar
  • 62 Garagorri J-M, Job J-C, Canlorbe P, Chaussain JL. Results of early treatment of cryptorchidism with human chorionic gonadotropin. J Pediatr 1982; 101 (6) 923-927
    CrossrefPubMedGoogle Scholar
  • 63 Biers SM, Malone PS. A critical appraisal of the evidence for improved fertility indices in undescended testes after gonadotrophin-releasing hormone therapy and orchidopexy. J Pediatr Urol 2010; 6 (3) 239-246
    CrossrefPubMedGoogle Scholar