Equine Veterinary Journal ISSN 0425-1644 DOI: 10.1111/evj.12116

Can and should we do more to reduce the incidence of cryptorchidism? In this issue, Almeida et al. [1] report on the effects of cryptorchidism on testicular maturation in young stallions and, in so doing, indirectly raise the question of where we currently stand with respect to our understanding of the causes and consequences of this common developmental abnormality in male horses. Cryptorchidism is a condition that the vast majority of equine practitioners will either have to deal with or advise on. However, given that the majority of colts will be gelded before they reach maturity, the focus of this attention will, in most cases, be on how best to remove the errant testicle. In this light, it is not surprising that recent innovation and developments relating to equine cryptorchidism have largely concentrated on optimising techniques for locating a retained testicle (e.g. transabdominal ultrasonography) [2] and on minimally invasive surgical approaches for removing or devitalising the offending organ [3]. Clearly, cryptorchidism is at best a considerable ‘inconvenience’ to both animal and owner. It is therefore surprising that we still have relatively few hard facts about the underlying causes and the potential (short- or long-term) consequences of testicular retention; this makes it difficult to give evidence-based advice on how to deal with cryptorchid colts that the owner does not wish to geld. There is, for example, no universal policy among studbooks and breeding organisations on whether unilateral cryptorchids should be considered acceptable for registration as breeding stallions or not, primarily because there is no conclusive proof that equine cryptorchidism is moderately to highly heritable. Even if evidence does emerge of a gene defect that predisposes to cryptorchidism, it seems unlikely that the same underlying mutation will be responsible for cryptorchidism in all horse breeds, just as it is unlikely that all phenotypic forms of cryptorchidism will have the same underlying cause(s). The assumption that cryptorchidism has a hereditary component is largely based on evidence that the condition is heritable in other species, and evidence that targeted mutations in, or knockout of, certain genes results in failure of testicular descent in mice [4]. The possibility of a hereditary component to equine cryptorchidism is supported by observations of an over-representation of some breeds (e.g. Percheron, American Saddle Horse and American Quarter Horse) among hospital admissions for cryptorchid castration [5] and reports of a high incidence of cryptorchidism in some breeds (e.g. 15% of Friesian colt foals) [6]. One mechanism proposed to contribute to hereditary cryptorchidism in nonequine species is abnormal expression of the insulin-like hormone INSL3, or its receptor (LGR8) [4], where INSL3 appears to be critical to gubernaculum growth and development, and thereby the intra-abdominal component of testicular descent (i.e. migration from the caudal pole of the kidney to the internal inguinal ring). However, whereas Klonisch et al. [7] demonstrated the presence of INSL3 and LGR8 in equine testes, and Pujar and Meyers-Wallen [8] demonstrated the existence of single nucleotide polymorphisms (i.e. gene mutations) in the LGR8 gene of phenotypically normal horses, there is as yet no definitive proof of a role for mutations in these or other genes in equine cryptorchidism. Indeed, the fact that approximately 85–90% of cryptorchid colts are unilaterally affected [9] complicates the picture further because it suggests that, even if a cryptorchidism-associated gene defect does exist, it predisposes to retention rather than guaranteeing failed descent. If this is the case, it follows that there will be phenotypically normal stallions (i.e. with 2 scrotal testes) that nevertheless carry the genetic predisposition to cryptorchidism and thereby suggests that selection based purely on phenotypic classification may not be very rewarding. Of course, accurate estimation of the degree of heritability of a given form of cryptorchidism within a given breed should help answer the question of the likely value of phenotypic selection, without the absolute need to identify the gene(s) involved. With respect to the possibility of covert carriers of a putative cryptorchidism gene, it is possible that the not uncommon phenomenon of delayed testicular descent in stallions may be a variant of inguinal retention; this possibility argues for the development of genetic tests to help identify carriers of any gene defect conclusively and use this Equine Veterinary Journal 45 (2013) 531–532 © 2013 EVJ Ltd

information to improve the efficacy of any programmes aiming to ‘select out’ cryptorchidism. A possible complication to any search for cryptorchidism-related genes is that, because the various events that contribute to testicular descent are controlled by different genes, there is a reasonable likelihood that abdominal and inguinal cryptorchidism are genetically unrelated conditions, and that more than one gene defect will be associated with cryptorchidism in different breeds; furthermore, it is probable that some cases of cryptorchidism will prove to be completely unrelated to any cryptorchidism-related gene defect and instead to have arisen incidentally as a result of other developmental accidents, for example prenatal testicular teratoma formation or cystic dilatation resulting in a testicle too large to pass into the nascent inguinal canal. In this respect, the task of identifying and confirming gene defects that predispose to cryptorchidism may not be straightforward, and initial steps will almost certainly require genome-wide genetic mutation analysis (e.g. using single nucleotide polymorphism chips) to detect regions of interest in a well-defined group of horses, in terms of phenotype (inguinal or abdominal cryptorchidism without other abnormalities) and bloodline. Ideally, the control population should come from a ‘cryptorchidism-free’ genetic line of the same breed. Extrapolation of the genetic background of cryptorchidism from one breed to another will require careful validation. Determining whether there is a hereditary component to cryptorchidism is, of course, critical to any meaningful discussion on the ethics of attempting to ‘assist’ testicular descent, either hormonally or surgically. Even if the ultimate conclusion is that assisted descent is acceptable (e.g. because the condition turns out not to be highly heritable), without a clear idea of the short-term consequences of testicular retention it is difficult to predict whether assisted descent is likely to be more successful than a ‘watch and wait’ approach with regard to the desired end-product, namely a normally sized and spermatogenetically functional scrotal testis. Understanding the effects of retention on testicular development is thus crucial when attempting to give evidence-based advice about whether a testicle that finally descends into the scrotum in a 2- to 3-year-old colt still has the capacity to develop into a grossly normal testicle. This explains the value of the report by Almeida et al. [1] that the retained testicles from 2- to 3-year-old cryptorchids maintain the molecular characteristics of prepubertal testes. This suggests that retention leads to a delay in development without, at least during the first 3 years, loss of the potential to develop spermatogenetic capacity if and when relocated to a suitable environment, i.e. the scrotum. This supposition is supported by the report by Turner et al. [10] that tissue fragments from the retained testicles of 1- to 4-year-old cryptorchids were able to initiate spermatogenesis after grafting under the skin of immunocompromised mice. Both of these studies imply that there is merit in waiting for testicular descent for at least 3 years in the case of inguinal cryptorchids and, if descent occurs, allowing further time for the affected testicle to recover. In contrast, neither study has any bearing on the question of whether breeding from unilateral cryptorchids and/or animals that had late testicular descent (assisted or not) contributes to the high incidence of cryptorchidism in some breeds. In short, the study by Almeida et al. [1] is a useful addition to the literature on the effects of cryptorchidism on testicular development and maturation, but also a useful reminder that there is still a lot of research to be done to establish how large a role heritable genetic mutations play in equine cryptorchidism and how widespread any genetic predisposition(s) currently is, in order to determine whether cryptorchidism-associated genetic mutations differ between horse breeds and/or phenotypic forms of cryptorchidism, and to determine whether there are any firm grounds for promoting phenotypic selection against cryptorchidism or whether selection should instead be based on genetic testing; any proposal should be supported by a prediction of how successful attempts to select against cryptorchidism are likely to be. Although there are therefore considerable



challenges to be met, the sequencing of the equine genome and subsequent development of techniques for genome-wide gene mutation screening means that these hurdles are considerably less daunting than they were a decade ago. T. A. E. Stout Department of Equine Sciences, Utrecht University, The Netherlands

References 1. Almeida, J., Conley, A.J. and Ball, B.A. (2013) Expression of anti-Müllerian hormone, CDKN1B, Connexin 43, androgen receptor and steroidogenic enzymes in the equine cryptorchid testis. Equine Vet. J. 45, 538-545. 2. Schambourg, M.A., Farley, J.A., Marcoux, M. and Laverty, S. (2006) Use of transabdominal ultrasonography to determine the location of cryptorchid testes in the horse. Equine Vet. J. 38, 242-245.


T. A. E. Stout

3. Hendrickson, D. (2006) Laparoscopic cryptorchidectomy and ovariectomy in horses. Vet. Clin. North Am. Equine Pract. 22, 777-798. 4. Basrur, P.K. (2006) Disrupted sex differentiation and feminization of man and domestic animals. Environ. Res. 100, 18-38. 5. Hayes, H.M. (1986) Epidemiological features of 5009 cases of equine cryptorchidism. Equine Vet. J. 18, 467-471. 6. De Nooij, H. (2012) Friesian cryptorchidism. Tijdschr. Diergeneeskd 137, 406-407. 7. Klonisch, T., Steger, K., Kehlen, A., Allen, W.R., Froelich, C., Kauffold, J., Bergmann, M. and Hombach-Klonisch, S. (2003) INSL3 ligand-receptor system in the equine testis. Biol. Reprod. 68, 1975-1981. 8. Pujar, S. and Meyers-Wallen, V.N. (2012) Sequence variations in equine candidate genes for XX and XY inherited disorders of sexual development. Reprod. Domest. Anim. 47, 827-834. 9. Edwards, J.F. (2008) Pathologic conditions of the stallion reproductive tract. Anim. Reprod. Sci. 107, 197-207. 10. Turner, R.M., Rathi, R., Honaramooz, A., Zeng, W. and Dobrinsky, I. (2010) Xenografting restores spermatogenesis to cryptorchid testicular tissue but does not rescue the phenotype of idiopathic testicular degeneration in the horse (Equus caballus). Reprod. Fertil. Dev. 22, 673-683.

Equine Veterinary Journal 45 (2013) 531–532 © 2013 EVJ Ltd

Can and should we do more to reduce the incidence of cryptorchidism?

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