The controversy regarding the need for hormonal treatment in boys with unilateral cryptorchidism goes on: a review of the literature Barbara Ludwikowski & Ricardo González
European Journal of Pediatrics ISSN 0340-6199 Eur J Pediatr DOI 10.1007/s00431-012-1711-y
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Author's personal copy Eur J Pediatr DOI 10.1007/s00431-012-1711-y
REVIEW
The controversy regarding the need for hormonal treatment in boys with unilateral cryptorchidism goes on: a review of the literature Barbara Ludwikowski & Ricardo González
Received: 8 December 2011 / Accepted: 27 February 2012 # Springer-Verlag 2012
Abstract Hormonal treatment for unilateral undescended testes continues to be recommended in some countries. We reviewed the literature in favor and against this recommendation. Since the paternity rate of men with a history of unilateral undescended testes only treated with surgery is normal, the effectiveness of hormonal treatment to produce testicular descent is low, the cost is considerable, and there are potential adverse effects, hormonal treatment for boys with unilateral undescended testes should no longer be recommended. Keywords Undescended testis . Cryptorchidism . Hormonal treatment . Orchidopexys
Undescended testis (UDT) affects 2–4% of newborns and often requires surgery to place the gonad in the scrotum (orchidopexy). Based on the observation that histologic changes in the UDT worsen with age, it is currently recommended that treatment should be completed before
B. Ludwikowski : R. González Kinderchirurgie und Kinderurologie, Kinderkrankenhaus auf der Bult, Janusz-Korszak-Allee 12, Hannover, Germany R. González Kinderurologie, Kinderspital Univesität Zürich, Steinwiesstrasse 75, 8032 Zürich, Switzerland R. González (*) Department of Urology, Thomas Jefferson University, Philadelphia, PA, USA e-mail:
[email protected]
age 18 months. Early orchidopexy leads to better growth of the testis [23] and reduces future risk of malignancy [33]. The theoretical basis for hormonal replacement therapy with human gonadotropin (HCG) or the LHRH analog buserelin rests on the hypothesis that in children with UDT, the normal hormonal surge which occurs around 3 months of age (minipuberty) is blunted thus hindering germ cell maturation [19]. Replacement therapy is used to correct this deficit which might lead to future infertility. Although the fertility potential of men with a history of bilateral UDT is clearly impaired regardless of treatment [11], the paternity rate of men who had unilateral UDT is normal [1, 15, 27]. Therefore, it continues to be a matter of debate whether hormonal treatment has a place in the management of boys with unilateral UDT. For example, the German guidelines for management of UDT available online (www.awmf.org/ leitlinien/detail/ll/ 006-022.html) [29] and a recent review article from England [4] recommend that hormonal treatment prior or after orchidopexy should be considered. Likewise, 25% of children in Italy receive hormonal treatment before or after orchidopexy [28]. In contrast, the Nordic consensus [37] and the Swiss [16] guidelines among others [6] state that hormonal treatment for this condition is ineffective and should not be recommended. Since hormonal treatment has some potential disadvantages including cost, potential undesirable side effects [6, 14, 40], and potential delay of surgery, we reviewed the evidence for and against its use. We searched for evidence for or against the following hypothesis: (1) UDT is an endocrinopathy, (2) hormonal replacement corrects the endocrinopathy and improves fertility, and (3) fertility and paternity are impaired in unilateral cryptorchidism. To avoid confounding information, we limit this review to unilateral UDT.
Author's personal copy Eur J Pediatr
Methods We searched PubMed using the following key words: cryptorchidism and hormonal treatment, undescended testes and hormonal treatment, Buserelin and undescended testis, paternity and cryptorchidism, fertility and cryptorchidism (since 2007), minipuberty, and sex hormone surge in undescended testis. We also searched through the references of the selected articles and reviewed the ones that appeared pertinent. All abstracts yielded were read, and the full-length articles of the selected abstracts were reviewed.
Results PubMed search yielded 882 abstracts in the following categories: cryptorchidism and hormonal treatment 296 abstracts, undescended testes and hormonal treatment 298 abstracts, Buserelin and undescended testis 20 abstracts, paternity and cryptorchidism 34 abstracts, fertility and cryptorchidism (since 2007) 215 abstracts, minipuberty 7 abstracts, and sex hormone surge in undescended testis 12 abstracts. Duplicates were eliminated. All abstracts that included controlled studies and those which provided useful information were included. The authors discussed and agreed on which articles should be included in this review. For the sake of clarity, we shall discuss our analysis of the literature in sections. Hypothesis 1: UDT is an endocrinopathy The surge in sex hormones that normally occurs around 3 months of age [17] may influence the infant testes and the maturation of spermatogonia. Some authors have reported that in children with UDT, the hormone surge at 3 months of life is blunted [22], but others have failed to corroborate this observation [3, 12]. Others postulated a deficiency in FSH production in some children with UDT that will ultimately be infertile [9]. The differences between reports may be related to timing of the samples, different populations, choice of controls, or the bioactivity of androgens, which seems to be decreased in boys with high UDT [35]. It is assumed that the increase in the number of dark spermatogonia (Ad spermatogonia) observed after 5 months of life in normal boys is driven by the sex hormone surge. In contrast, this increase in the number of Ad spermatogonia was completely absent in the UDT [18]. Hadziselimovic et al. also reported that the contralateral scrotal testis also exhibits a decrease in the number of Ad spermatogonia which may influence future fertility [20]. Suomi et al. proposed that UDT patients have a mild testicular dysfunction already present in the fetus and questioned whether this was a cause or a consequence of cryptorchidism [39]. Most authors agree that although an endocrinopathy may
be responsible for UDT in some children, the pathogenesis and etiology is likely multifactorial and in most cases unknown [2, 41]. Hypothesis 2: Hormonal replacement corrects the endocrinopathy Hormonal treatment for UDT was first recommended by a Latvian andrologist, Bernhard Schapiro, working in Berlin in the 1930s [5]. The original intent was to produce testicular descent; however, numerous studies have determined that this occurs in only 20% of the cases and reascent occurs in 15% of the cases [34]. The modern basis for recommending hormonal treatment alone or as an adjuvant to orchidopexy derives mostly from the work of Hadziselimovic [20]. In many of his publications, this author made the observation that UDT in children treated with GNRH agonists has a greater number of Ad spermatogonia, a finding interpreted as more favorable to future fertility. The fertility index is based on this count of the testicular biopsies [20]. This observation has been corroborated by others [21, 24, 38]. What has not yet been proven is those histological changes that result in impaired fertility in unilateral UDT. Also, it is not known if whether or not this increase in the number of Ad spermatogonia is transient or long lasting. In 2007, Hadziselimovic et al. published a paper entitled “Infertility in Cryptorchidism is Linked to the Stage of Germ Cell Development at Orchidopexy” [20] in which 218 formerly cryptorchid men operated in childhood after failed hormonal treatment were studied. They had testicular biopsies at the time of surgery, and they provided semen for analysis. The authors state that “Abnormal sperm concentration (
