European Review for Medical and Pharmacological Sciences 2009; 13: 351-356 and its long-term complications

S. LA VIGNERA, A.E. CALOGERO, R. CONDORELLI, A. MARZIANI*, M.A. CANNIZZARO*, F. LANZAFAME**, E. VICARI

Andrology and Reproductive Endocrinology Unit, Garibaldi Hospital, University of Catania (Italy) *Endocrine Surgery Unit, S. Luigi Hospital, University of Catania (Italy) **Territorial Center of , A.U.S.L. 8, Syracuse (Italy)

Abstract. – Cryptorchidism is the most risk factor for primitive testiculopathy, showing a frequent defect of the male urogenital tract at potential wide frame of altered , birth. It represents a risk factor for primitive tes- associated with long-term functional-like compli- ticulopathy associated with long-term complica- cations (infertility), and/or degenerative-organic tions (infertility, testicular neoplasia, and hor- 2 monal changes). An only consensus exists: ones (testicular neoplasia). Since Charny under- “children with bilateral cryptorchidism who are lined that “orchidopexy techniques have regis- not treated in early age are certainly set to be- tered a progressive and satisfying improvement come infertile”. The majority of Authors agrees of the cosmetic result, but testicular functional that the cryptorchid will be in for struc- result has not reached the target which has been tural and functional alterations and the rate of set”, few achievements have been made during infertility is inversely proportional to the age at the time of orchidopexy. Cryptorchidism causes the years. As matter of fact, although the effects secretory primitive testicular pathology respon- of spermatogenesis and the future of the sible for infertility. It is correlated to a non-spe- patient with a history of cryptorchidism have cific severe histopathological pattern that can be been studied in an extensive way, scientific opin- useful to predict future infertility at the moment ion has reached an only consensus: “children of orchidopexy. Also cryptorchidism represents with bilateral cryptorchidism who are not treated the major risk factor associated with testicular neoplasia (5-10 times more probably in early age are certainly set to become infertile”. than a normal testicle) due to genetic, hormonal, The majority of the Authors agree on two other environmental factors. aspects3-5: a) the cryptorchid testicle will be in for structural and functional alterations; b) the Key Words: rate of infertility is inversely proportional to the Cryptorchidism, , Testicular neoplasia. age of the patient at the time of orchidopexy. The logical conclusion to this point of view is believ- ing that problems due to infertility, secondary and cryptorchidism, could have been simply managed by anticipating orchidopexy before the age of 2. Unfortunately, after 30 years since re- sults on fertility following early age orchidopexy Introduction are available, the therapeutic strategy for operat- ing before the age of 2 has not reached an unani- Non syndromic (simple) cryptorchidism is the mous consensus. The follow-up results have reg- most frequent defect of the male urogenital tract istered a wide range infertility rate, correlated to at birth. It occurs when the testicle fails to de- the past of both bilateral (28.5-82%) and mono- scend from the lumbar region to the dur- lateral (62-74%) cryptorchidism3,4, and to the ing natural migration: in 2-4% of full-term and in complications due to long-term cryptorchidism 20-30% of premature births. The estimated need (fertility and testicular neoplasia) based on the for orchidopexy concerns about 27,000 cases per region, side and age at the time of orchidopexy6. year in the US1. Simple and syndromic cryp- It is estimated that about 20% of the patients who torchidism have several causes (Table I e II). Al- have undergone orchidopexy at are at though cryptorchidism is considered a “modest risk for future paternity even after TESE-ICSI, malformation”, it represents a well-characterized due to a “real testicular ”7. Cryp-

Corresponding Author: Alessia Marziani, MD; e-mail: [email protected] 351 S. La Vignera, A.E. Calogero, R. Condorelli, A. Marziani, M.A. Cannizzaro, F. Lanzafame, E. Vicari

Table I. Causes of non syndromic cryptorchidism.

Mechanical factors Endocrine factors

Inguinal canal obliteration Low/absent GnRH Fibrous septum between internal inguinal ring and scrotum Dysgenesis/ Brevity of spermatic funicle elements biosynthetic problems MIF deficiency/persistent Mullerian ducts 5 α reductase deficiency resistance

torchidism pathogenesis is still uncertain, but it’s gestational month to birth or shortly after)9. Dur- supported by one or more of the following fac- ing the first year of life, cryptorchid child don’t tors: anatomical (peritoneal adhesions, mesorchi- show functional deficiency relating to hypothala- um brevity, spermatic vessels and deferent duct mus-pituitary-testicular axis nor changes in brevity, tight , external inguinal testosterone biosynthesis10. In pre-pubertal and, ring obstruction), hormonal (hypothalamus-pitu- especially, in post-pubertal age FSH ed LH levels itary deficiency) and dysgenic primitive testicu- depend on testicular hormones production lar. Pathogenesis affects the hormonal balance (testosterone and inhibin B), reflecting testicular (FSH, LH, ), which mediate testicular hystopathology. Plasma FSH levels generally in- migration during gestational age by the anti-Mül- crease in those men with severe and lerian hormone and the androgen dependent fac- mycro-orchidism (testicular size <12 ml). Plasma tors, such as the insulin like 3 (INSL3) produced LH and testosterone levels are usually normal, by the Leydig cells. INSL3 acts through a G-pro- but mean basal and peak GnRH-stimulated LH tein coupled receptor, LGR8 (leucine-rich repeat- levels are slightly higher than normal, suggesting containing G protein-coupled receptor 8), stimu- subtle dysfunction11. Syndromic lating gubernaculum growth8 and/or direct or in- cryptorchidism represents an aspect of hereditary direct androgenic action through calcitonin - syndromes characterized by hormonal changes, related peptide release from genito-femoral nerve such as constant or occasional hypogonadism (during the trans-inguinal phase: from seventh (hypogonadotropic or hypergonadotropic) and/or

Table II. Syndromic Cryptorchidism.

Frequent in syndromes (s) Occasional in syndromes (s)

Aarskog’s Cockayne’s Carpenter’s Coffin-siris’ Fraser’s (cryptophthalmos) Cri-du-chat’s. Nevoid basal cell carcinoma syndrome (Gorlin’s) Achondroplastic dwarfism Lowe’s Down’s Meckel-Gruber’s Fanconi’s Noonan’s Femoral hypoplasia-unusual facies’s. Opitz’s Hallermann-Streiff’s. Roberts’s Steinert myotonic dystrophy Robinow’s Prader-Willi’s. Rubinstein-Taybi’s Saethre-Chotzen’s. Seckel’s Trisomy 8 s. Smith-Lemli-Opitz’s XXY s. Triploidy s. XYY s. Trisomy 13 s. Zellweger’s. Trisomy 18 s. –21q s. –4p s. –13q s. –18q s.

352 Cryptorchidism and its long-term complications testosterone biosynthesis or androgenic action tubules having a -only syndrome”. defect, and more or less complex genetic alter- According to a recent study15 carried out on 18 ations. All these factors accounts for the frequent patients who underwent testicular biopsy during or occasional occurrence of cryptorchidism al- orchidopexy and then again in adulthood aimed ways due to multiple congenital alteration both at expanding on infertility, the alterations of sper- somatic and nervous (CNS) (Table II). matogenesis observed in prepubertal biopsies were generally classified as type I (modest alter- ations), II (marked germinal hypoplasia), and III Complications after long-term (severe germinal hypoplasia). cryptorchidism Instead, the alterations of spermatogenesis in biopsies carried out in adulthood where divided Infertility into lesions of the adluminal compartment or of Cryptorchidism is included among the causes the basal compartment of seminiferous tubules, of secretory kind primitive testicular pathologies by comparing the prepubertal biopsy frame of which are responsible for infertility due to a each patient versus the postpubertal one. The Au- “male factor”. The predisposing factors seem to thors noticed that the recurrent frame (responsi- be due genetic, hormonal (testosterone, genetic ble for infertility) of mixed testicular was alterations of the insulin-like factor 3) and/or en- that of type III with incomplete spermatogenesis vironmental purposes12. (p<0.0001) and more severe lesions of the germi- Although there is no specific cryptorchidism nal epithelium (p=0.049). Type III lesions corre- pathognomonic histopathological pattern exist- lated with a frame of mixed testicular atrophy al- ing, the factor discriminating future fertility is so conferred the worst prognosis in the programs the presence of Ad spermatogonia at the time of of assisted reproductive technology (ART)15. On orchidopexy4. Therefore, testicular biopsy the other hand, a diametrically opposed histo- histopathology when performing orchidopexy pathological situation to the ones described3,4,14,15 can show useful information to predict future fer- and less severe one, already witnessed by Berga- tility13. da et al16 and verified in another subgroup of pa- As a matter of fact, future infertility of the tients with previous cryptorchidism, would justi- cryptorchid is associated with a particular severe fy the results of a recent retrospective study17, anatomopathological testicular secretory frame carried out on 142 azoospermic patients and pre- which can already be observed in a young cryp- viously suffering cryptorchidism (71.8% treated torchid3,4,14: 0 Ad spermatogonia (dark), and <0.2 with orchidopexy before the age of 10), who un- germ cells/transverse tubular section (v.n. derwent TESE (testicular sperm extraction) be- >2/transverse tubular section). Then, according tween 1995-2005, during medical assisted pro- to some studies4,14, the above-mentioned severe creation (PMA) through ICSI (intracytoplasmic anatomopathological testicular secretory frame is sperm injection). In this study, the prognosis of significantly correlated (p<0.001) in time with: a) nemaspermatic recovery is considered good, a reduced nemaspermatic production (average: since all together it is equal to 65%, and in par- 8.9 × 106 spermatozoons /ejaculated), 25 times ticular, 63% (55/87) of patients with a history of less compared to the group of controlled cryp- bilateral cryptorchidism, and 61.9% (36/42) of torchids (showing Ad spermatogonia in both tes- patients with a history of monolateral cryp- ticles during biopsy performed at the time of or- torchidism. The Authors of this study have as- chidopexy); b) azoospermia in 20%. Moreover, serted that a predictive value for the recovery was since 70% of the patients with monolateral cryp- represented by normal FSH values and testicular torchidism shows an improper transformation of volume >10 ml17. Ad spermatogonia, some Authors classify cryp- torchidism as a bilateral disease4,14. Pathogenetic Mechanisms Another histo-pathological pattern which can Responsible for Infertility Correlated frequently be observed in biopsies regarding to Cryptorchidism crypthorchid is mixed testicular atrophy, It is believed that infertility induced by cryp- defined as “synchronous, contemporary and of torchidism is an endocrinopathy whose main variable proportions, a presence of seminiferous cause is recognized as an “impaired” mini-pu- tubules including both a normal progressive sper- berty18, defined as a hormonal risk factor peak matogenetic maturation of the germ cells and period of occurring during early

353 S. La Vignera, A.E. Calogero, R. Condorelli, A. Marziani, M.A. Cannizzaro, F. Lanzafame, E. Vicari childhood, which is necessary and important to some clinical and biological risk factors (low induce the development and transformation of weight at birth; urogenital congenital deformity: into Ad spermatogonia3,5,14,18-21. As a cryptorchidism, )25-27. As the precur- matter of fact, this period is insufficient and inad- sor of seminomatous neoplasia (SEM), nonsemi- equate in about 50% of the testicles of cryp- nomatous germ cell testicular neoplasia torchid subjects in the inguinal region and in (NSEM), as well as certain types of germ cell 90% of the testicles situated in the intra-abdomi- neoplasia in the extragenital region (retroperi- nal region18. In order to correct this mini-puberty toneal, mediastinic, CNS), carcinoma in situ or imperfection, some Authors have shown that a 5 CIS has several cytological features in common month alternate-day medication before the age of with foetal germ cells28,29. Therefore, from a six immediately following orchidopexy of LH- clinical point of view, in post-orchidopexy fol- RH analogue () does not inhibit go- low-up, besides clinical evaluation another im- nadotropin secretion and assures higher LH val- portant adjuvant role is played by diagnosis ues at the end of treatment21, but above all it de- through diagnostic imaging with scrotal ultra- termines an increase in the number of spermato- sonography. Apart from providing information genetic germ cells (versus a control group under- on echo-sounding and reduced echostructure of going orchidopexy only)3,5,14,18-20. the previous cryptorchid testicle, it may reveal the presence of areas of microlithiasis which Neoplastic Degeneration should not be considered as a rare report but (Testicular Neoplasia) rather deserves being monitored since the risk of Cryptorchidism represents the major risk fac- turning itself into a carcinoma affecting these ar- tor associated with germ cell testicular neoplasia eas is significant30,31. According to what has (seminomatous, SEM; non seminomatous, been said, testicular biopsy is the only diagnos- NSEM). These types of neoplasia have a 5-10 tic procedure to identify patients at risk of future times more probability of outbreak in the cryp- infertility, and/or candidates in line for treatment torchid testicle compared to a normal one. This with GnRH analogue following orchidopexy. risk becomes higher the higher the region of tes- Unfortunately, material regarding biopsy which ticle descent is (abdominal vs. inguinal)22. The is studied and published in literature is influ- wide range as a risk factor (OR 2.9-11) for tes- enced by a selection bias, since it derives from: ticular neoplasia of cryptorchidism depends on the multiple pathogenetic mechanisms (genetic, a) cryptorchid testicles which are non responsive hormonal, environmental ones) which are re- to hormonal therapy, and therefore subjected sponsible for a certain kind of cryptorchidism. later on to orchidopexy; The major degenerative risk factors can be found b) cryptorchid testicles which have never been in TDS (testicular dysgenesis syndrome)23 pre- treated with hormonal therapy, and directly senting some of the peculiar common features: treated with surgery. pathogenetic hypothesis [disturbed gonadal de- velopment in fetal age by one or more: genetic As a matter of fact, there is no possibility to factors (family OR = 3.8 with a testicular neo- carry out a quantitative analysis of spermatoge- plasia carrying father; OR = 7.6 with a testicular nesis directly on those subjects who have neoplasia carrying brother)24; subjection to en- reached testicular descent after medical treat- docrine disruptors, such as constant polluting ment. Therefore, it is not possible to obtain any organics, pesticides, phthalates); motherly life results on functionality in this group since the style (smoking), phenotype at birth (cryp- clinical-anatomical result which has been torchidism, hypospadias), long-term complica- reached is not simply cosmetic, like that follow- tions such as infertility, and/or testicular neopla- ing orchidopexy. At this point it is possible to sia (in more severe forms)]25. The different final understand how long-term results only, by using testicular expression resulting is due to the dif- the seminologic analysis combined with second ferent interaction between the altered/destroyed level evaluations (chromatin compaction, frag- scheduling of embryo-foetal development re- mentation of spermatic DNA, early apoptosis garding the male gonad and to the adverse pre- markers) besides echographic monitoring, based or post-natal gonadotropic environmental influ- on the age of the patient at the time of treatment ences. On the other hand, foetal origin testicular (hormonal and/or surgical). These exams are neoplasia is supported by the association with able to indicate if and how some factors (such

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