Infertility in Cryptorchidism Is Linked to the Stage of Germ Cell Development at Orchidopexy

Hadžiselimović, Faruk; Höcht, B.; Herzog, B.; Buser, Marc

doi:10.1159/000100874

Cited by 104 publications

(103 citation statements)

References 34 publications

(23 reference statements)

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“…The risk of testis cancer is significantly decreased if orchidopexy for undescended testis is performed before puberty (60). In reality, it is recommended that orchidopexy is undertaken as early as 6-12 months of age to ensure the optimal germ cell development that occurs during the first year of life (61,62).…”

Section: Environmental Factorsmentioning

confidence: 99%

Factors controlling testis descent

Hughes¹,

Acerini²

2008

European Journal of Endocrinology

139

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Descent of the testis from an intra-abdominal site in foetal life to an extracorporeal location after birth is a mandatory developmental process to ensure that the mature testis promotes normal spermatogenesis. The two phases of transabdominal and inguinoscrotal descent occur approximately during the first and last thirds of gestation respectively. Key anatomical events to release the testis from its urogenital ridge location and to guide the free gonad into the scrotum are the degeneration of the cranio-suspensory ligament and a thickening of the gubernaculum. Androgens play a role in both these processes, particularly with respect to enabling the testis to traverse the inguinal canal in the final phase of descent. Experiments in animals suggest that androgens mediate this effect via the release of calcitonin gene-related peptide by the genitofemoral nerve, but direct evidence for such a mechanism is lacking in humans. The transabdominal phase of descent is under the control of insulinlike 3 (INSL3), a product of the Leydig cells. Definitive evidence of its role in rodent testis descent is illustrated by the phenotype of bilateral cryptorchidism in Insl3K/K null mice. Circulating levels of INSL3 are higher in boys at puberty, are undetectable in girls and are lower in boys with undescended testes. A minority also have a mutation either in the INSL3 gene or affecting its receptor gene, relaxin/insulin-like family peptide receptor 2 (LGRF8). Other factors that may play a role in testis descent include the anti-Mullerian hormone and members of the HOX gene family. Evidence that the prevalence of undescended testis may be increasing provides a phenotypic readout for the effects of postulated chemicals in the environment interfering in some way with the action of factors that control testis descent. Epidemiological studies point to profound geographical variations in prevalence in countries such as Denmark and Finland. Associations have been found with levels of chemicals labelled as endocrine disruptors being higher in breast milk samples from mothers with cryptorchid boys when compared with controls. The adverse effects of these compounds (e.g. bisphenol A) can be replicated in the offspring of dams exposed during pregnancy. A sensitive marker of an anti-androgen effect of a compound is a reduction in the anogenital distance, an anthropometric measurement that is significantly greater in males compared with females. The observation of an association between the anogenital distance in infant boys and the level of pesticides in the urine of their mothers in late gestation indicates that this has the potential to be a useful surrogate marker of the effects of environmental chemicals on testis descent in human population studies. The rightful place for the testis at birth is in the scrotum in order to provide the temperature differential essential for normal spermatogenesis. Appropriate screening programmes and early surgical intervention are the prerequisites to ensure optimal fertility in adulthood and a con...

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Section: Environmental Factorsmentioning

confidence: 99%

Factors controlling testis descent

Hughes¹,

Acerini²

2008

European Journal of Endocrinology

139

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“…Therefore, whether or not the patient will achieve normal fertility following successful surgery depends mainly upon the presence of Ad spermatogonia at the time of orchiopexy (4,11). At least half of cryptorchid population undergoing surgery had no Ad spermatogonia and consequently were candidates for hormonal treatment (7).…”

Section: Commentsmentioning

confidence: 99%

“…At least half of cryptorchid population undergoing surgery had no Ad spermatogonia and consequently were candidates for hormonal treatment (7). It is known that a testis in an intra-abdominal position has in general bad testicular histology beyond one year of age, and that a testis in pre-scrotal position has a better or is more close to normal testicular histology (8,11). However, in all positions, although with different incidences, the testes with no Ad spermatogonia and < 0.2 germ cell per tubule could be observed.…”

Section: Commentsmentioning

confidence: 99%

“…This insufficient testosterone secretion is responsible for impaired transformation of gonocytes into Ad spermatogonia (4,5,11,(15)(16)(17). Additional rationale for LH-RHa treatment was based on the histological analyses of undescended testes in infancy (4,5,11,(15)(16)(17)(18)(19)(20). ment of impaired mini-puberty should be performed before this age.…”

Section: Commentsmentioning

confidence: 99%

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Successful treatment of unilateral cryptorchid boys risking infertility with LH-RH analogue

Hadžiselimović¹

2008

Int. braz j urol.

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Introduction: Infertility is the primary concern for boys with uni-or bilateral undescended testes. An early and seemingly successful orchiopexy does not improve fertility in a substantial number of cryptorchid males. We confirmed that LH-RH analogue (LH-RHa) treatment induces an increase in and maturation of the germ cells; however, it was uncertain if treatment would improve the chance of fertility later in life. Materials and Methods: Thirty unilateral cryptorchid boys, with an average age of 3 years at the time of surgery, were included in the study. Testicular biopsy showed that they had impaired testicular maturation and were therefore at high risk for infertility. Fifteen of the 30 unilateral cryptorchid boys were treated with 10 µg LH-RHa (Buserelin) nasal spray, administered on alternate days for a period of 6 months, following orchiopexy. The control group consisted of 15 cryptorchid boys who had been treated by Schoemakers type of orchiopexy, alone. After puberty, the ejaculates of both groups were analyzed. Results: All males in the untreated group were severely oligospermic, with 20% being azoospermic. In contrast, 86% of the treated ex-cryptorchid males had a sperm concentration within the normal range; this was significantly different from the sperm concentration found in the untreated group (p = 0.000008). Conclusion: For the first time, we demonstrate that infertility in cryptorchidism can be successfully corrected when suitably treated with a LH-RHa. Sperm parameters normalized following therapy in the majority of cryptorchid males who, untreated, would have remained infertile. This innovative hormonal treatment will have a profound effect on the current recommended surgical treatment of boys with undescended testes.

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“…Thus, cryptorchidism is one of the main etiologic causes of non-obstructive azoospermia in man [1]. Interestingly enough, in unilateral cryptorchid males, no significant differences in frequency of azoospermia was observed irrespective of the treatment modalities used (untreated, [4] while none (0/50) (p<0.000001) of the males with identical testicular pathology at surgery who received treatment with buserelin following orchidopexy developed azoospermia.…”

mentioning

confidence: 94%

The controversy regarding the need for hormonal treatment in boys with unilateral cryptorchidism goes on: a review of the literature by B. Ludwikowski and R. González

Hadžiselimović

2012

Eur J Pediatr

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Sir, In their review, Ludwikowski and González [5] discouraged the use of hormones in unilateral cryptorchid boys because (1) the paternity rate is normal in men with unilateral undescended testes treated with surgery alone, (2) the efficacy of hormonal treatment in inducing testicular descent is low, (3) the cost of the treatment is considerable, and (4) there are potential adverse effects associated with treatment.However, despite successful surgery, azoospermia is 25 times more common in unilateral and 80 times more common in bilateral cryptorchidism in comparison with the control population [2]. Thus, cryptorchidism is one of the main etiologic causes of non-obstructive azoospermia in man [1]. Interestingly enough, in unilateral cryptorchid males, no significant differences in frequency of azoospermia was observed irrespective of the treatment modalities used (untreated, 12 % [16/ 134] Therefore, since the endocrinopathy of mini-puberty is responsible for ensuing infertility in cryptorchidism, postsurgical hormonal treatment is highly recommended in cryptorchid boys who have early successful orchidopexy but remain at risk of infertility. Finally, hormonal treatment has been the choice of initial treatment (before surgery) in Europe for years. It abrogates the need for subsequent surgery, and for non-responders, it facilitates orchidopexy and contributes considerably to reducing the incidence of unilateral and bilateral complete post surgical testicular atrophy. References

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Infertility in Cryptorchidism Is Linked to the Stage of Germ Cell Development at Orchidopexy

Cited by 104 publications

References 34 publications

Factors controlling testis descent

Factors controlling testis descent

Successful treatment of unilateral cryptorchid boys risking infertility with LH-RH analogue

The controversy regarding the need for hormonal treatment in boys with unilateral cryptorchidism goes on: a review of the literature by B. Ludwikowski and R. González

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