Why Early Surgery May not be Enough: The Search for New Therapeutic Strategies in Cryptorchidism[*]

End point for the successful treatment of cryptorchid boys is fertility. There is consensus now between pediatric surgeons, pediatric urologists and pediatric endocrinologists, that treatment to bring the testes into the normal intrascrotal position must be initiated early, within the first year of life [1] [14]. These statements have a simple implication: In cryptorchidism research, up to 20 years of longitudinal follow-up may be required before conclusions from diagnostic or interventional studies can be drawn. In clinical science, such time dimensions exceed by far the short funding intervals currently provided for by the major grant programs. For young scientists, it is not necessarily first choice to start their research careers with prospective studies, where they would have to wait more than one decade to see their results published. Therefore, the number of researchers having the foresight, determination and resources to embark on long-dated projects is usually small. Faruk Hadziselimovic is one of these researchers.

Already in 1975 Hadziselimovic described pronounced Leydig cell atrophy starting in early infancy in boys with undescended testes. These data led him to formulate the hypothesis of impaired intrauterine and early postnatal gonadotropin secretion as the leading etiological factor of cryptorchidism [9]. In the following years, he further demonstrated

an exaggerated decrease of the number of germ cells in cryptorchid testes already in the second half of the first year of life, explaining the need for early surgical intervention 8 decreased maturation in the cryptorchid testes of gonocytes to adult dark (Ad) spermatogonia, which form the adult stem cell reservoir 6

Later, he and his coworkers provided evidence that this maturation is testosterone dependent and is disturbed in the majority of cryptorchid boys [12] [15].

As a consequence of his data and the data of others, the frequency of orchidopexies performed early, within the first year of life, increased worldwide. However, when the first patients who had undergone early surgery were investigated as adults, it was disappointing to see that some of these patients were infertile despite early intervention. Again, the Ad spermatogonia were identified as key players: 94% of men, who had Ad spermatogonia in the biopsies taken at the time of orchidopexy, had normal sperm counts. In contrast, 92% of men who did not have Ad spermatogonia at the time of orchidopexy, showed abnormal spermiograms [7]. The differences in adult sperm production after early orchidopexy could thus be explained by the presence or absence of Ad spermatogonia at the time of surgery.

In this issue of ‘Klinische Pädiatrie’, Faruk Hadziselimovic and Burckhardt Hoecht from the Department of Pediatric Surgery at the University of Würzburg, Germany, present another set of data [10] demonstrating the links between testicular histology at the time of childhood orchidopexy, and semen analysis and hormonal findings in adult life.

The authors report the results of a prospective study extending over 23 years. 89 men who had undergone orchidopexy and testicular biopsy in childhood, were reexamined. Basal gonadotropin and testosterone concentrations were measured and the spermiogram was evaluated. There are three key messages in this paper:

Unilateral cryptorchidism is a bilateral disease, affecting both testes The number of Ad spermatogonia at the time of orchidopexy is predictive of the sperm concentration in adult life The majority of men treated surgically in childhood for severe forms of cryptorchidism do have relative gonadotropin deficiency as adults.

How can that be, since the authors report slightly elevated FSH concentrations in their patients ? Hadziselimovic and Hoecht argue that like in patients with Klinefelter syndrome, showing a similar degree of testicular damage, FSH concentrations should be three to four times higher in their patients, the difference being explained by the relative FSH deficiency in cryptorchid patients extending from early infancy into adulthood.

There are other things that can be learned from this paper. First, if we do not perform testicular biopsies more frequently at the time of orchidopexy, we will not know what to expect in our patients, opportunities for further intervention could be missed. Second, if we do perform biopsies, we will need experienced pathohistologists as examiners. Evaluating testicular biopsies of children is not a daily routine anymore in most departments of pathology. It may even become necessary to establish reference institutions to whom the samples should be sent. Third, close cooperation is needed between all doctors caring for boys with undescended testes. The general pediatrician is responsible for early diagnosis. Together with an experienced pediatric endocrinologist, he will evaluate the infant for underlying endocrinopathies and perform medical treatment with hCG and gonadotropin releasing hormone or its analogues. If that fails, the pediatric urologist or pediatric surgeon will take over before the patient's first birthday to perform a biopsy and bring the testes into the scrotal position. Now it is the pathologist's turn to provide his colleagues with information regarding the Ad spermatogonia status for further intervention. Models of multidisciplinary co-operation like this have long been established by our colleagues, the pediatric oncologists. Their cooperation includes not only patient care but extends to multicenter studies, that aim at optimizing all forms of therapy [2] [3].

What further interventions beyond early surgery are available ? The most exciting data come from Hadziselimovic's studies where he continued GnRH treatment for some time after orchidopexy in an attempt to induce the testosterone rise that appears to be lacking in most infants with cryptorchidism. After post-surgery GnRH agonist treatment he saw a significant rescue of germ cells, giving rise to the hope that fertility could be preserved by this treatment [5].

As an advocate of medical treatment in combination with early surgery, Hadziselimovic has put himself into contrast to a current trend in European pediatric endocrinology and surgery. At least in the northern European countries, the ‘Nordic Consensus on treatment of undescended testes’ proposes to forbear from medical therapy and to rely solely on surgical intervention [13], one of the reasons being a possible increased rate of germ cell apoptosis after use of hCG. Hadziselimovic intervened in this highly controversial issue pointing out the germ cell rescue achieved by GnRH post-treatment and requested to cut the ban on medical treatment as stated in the Nordic consensus [11].

In their reply, the Nordic colleagues argued that none of Hadziselimovic's data so far had shown a positive effect of medical co-treatment on sperm analysis, but they also conceded: ‘In medicine, no recommendations on treatment are forever. When new convincing data are presented the recommendations [by the Nordic Consensus Group] will be modified.' This month, new data from Hadziselimovic were published in another journal [4] showing that adult spermatogenesis could indeed be improved after GnRH co-treatment of cryptorchidism in childhood.

Maybe the time to reopen the discussion on medical co-treatment of cryptorchidism has come right now.

1 A short comment on terminology: In the Anglo-American medical language, the term ‘cryptorchidism’ denotes all forms of undescended testes, from the intraabdominal to the inguinal position, sometimes including the high scrotal position. In Europe, the term ‘cryptorchidism’ is mainly reserved for a testis in the intraabdominal position. In this invited commentary, the term is used in the Anglo-American context.

References

• 1 AWMF Online . Leitlinien der Deutschen Gesellschaft für Kinderchirurgie, der Deutschen Gesellschaft für Urologie, der Deutschen Gesellschaft für Kinder- und Jugendmedizin, vertreten durch die Arbeitsgemeinschaft für pädiatrische Endokrinologie (APE). Hodenhochstand – Maldeszensus testis. AWMF-Leitlinien-Register Nr 006/022 (Entwicklungsstufe 2k). 2008;  http://www.uni-duesseldorf.de/awmf/ll/006-022.htm
• 2 Calaminus G, Kaatsch P. Positionspapier der Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) zu (Langzeit-)Nachbeobachtung, (Langzeit-)Nachsorge und Spätfolgenerhebung bei pädiatrisch-onkologischen Patienten.  Klin Padiatr. 2007;  219 173-178
• 3 Göbel U, Henze G. Therapieoptimierung, Risikostratifizierung und neue Therapieverfahren.  Klin Padiatr. 2006;  218 129-130
• 4 Hadziselimovic F. Successful treatment of unilateral cryptorchid boys risking infertility with LH-RH analogue.  Int Braz J Urol. 2008;  34 319-328
• 5 Hadziselimovic F, Herzog B. Treatment with a luteinizing hormone-releasing hormone analogue after successful orchiopexy markedly improves the chance of fertility later in life.  J Urol. 1997;  158 1193-1195
• 6 Hadziselimovic F, Herzog B. Importance of early postnatal germ cell maturation for fertility of cryptorchid males.  Horm Res. 2001;  55 6-10
• 7 Hadziselimovic F, Herzog B. The importance of both an early orchidopexy and germ cell maturation for fertility.  Lancet. 2001;  358 ((9288)) 1156-1157
• 8 Hadziselimovic F, Herzog B, Buser M. Development of cryptorchid testes.  Eur J Pediatr. 1987;  146 ((Suppl 2)) S8-12
• 9 Hadziselimovic F, Herzog B, Seguchi H. Surgical correction of cryptorchism at 2 years: electron microscopic and morphometric investigations.  J Pediatr Surg. 1975;  10 19-26
• 10 Hadziselimovic F, Hoecht B. Testicular Histology Related to Fertility Outcome and Postpubertal Hormone Status in Cryptorchidism.  Klin Padiatr. 2008;  220 302-307
• 11 Hadziselimovic F, Zivkovic D. Is the prohibition of hormonal treatment for cryptorchidism, as suggested by the Nordic consensus group, justifiable?.  Acta Paediatr. 2007;  96 ((9)) 1368-1369
• 12 Hadziselimovic F, Zivkovic D, Bica DT, et al . The importance of mini-puberty for fertility in cryptorchidism.  J Urol. 2005;  174 1536-1539
• 13 Ritzen EM, Bergh A, Bjerknes R. et al . Nordic consensus on treatment of undescended testes.  Acta Paediatr. 2007;  96 638-643
• 14 Thorsson AV, Christiansen P, Ritzen M. Efficacy and safety of hormonal treatment of cryptorchidism: current state of the art.  Acta Paediatr. 2007;  96 628-630
• 15 Zivkovic D, Bica DT, Hadziselimovic F. Relationship between adult dark spermatogonia and secretory capacity of Leydig cells in cryptorchidism.  BJU Int. 2007;  100 1147-1149

1 A short comment on terminology: In the Anglo-American medical language, the term ‘cryptorchidism’ denotes all forms of undescended testes, from the intraabdominal to the inguinal position, sometimes including the high scrotal position. In Europe, the term ‘cryptorchidism’ is mainly reserved for a testis in the intraabdominal position. In this invited commentary, the term is used in the Anglo-American context.

Correspondence