Vol. 10, No. 1

19

REVIEW

Cryptorchidism and long-term consequences Maciej Kurpisz1,2, Anna Havryluk3, Andriej Nakonechnyj4, Valentina Chopyak3, Marzena Kamieniczna2 2 Institute of Human Genetics, Polish Academy of Sciences, Department of Reproductive Biology and Stem Cells, Poznan, Poland; 3 Danylo Halytsky Lviv National Medical University, Department of Clinical Immunology and Allergology, Lviv, Ukraine; 4 Danylo Halytsky Lviv National Medical University, Department of Pediatric Surgery, Lviv, Ukraine Received: 8 September 2009; accepted: 29 January 2010

SUMMARY Cryptorchidism has been on the rise for several decades and can be observed with frequency of 1-2% of males within the first year of age. It may appear as an isolated disorder or can be a consequence of genetic and endocrine abnormalities connected with somatic anomalies. Its genetic background still seems to be unclear although a range of genes can be responsible for the development of this syndrome. Cryptorchidism can be associated with serum testosterone level although the often co-existing hypogonadotropic hypogonadism may also indicate the involvement of pituitary hormones. Recently, environmental factors have been blamed for cryptorchidism induction. Autoimmune reactions in conjunction with steroid hormones regulating immune response can be also partly responsible for cryptorchiCorresponding author: Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479 Poznan, Poland; e-mail: [email protected]

1

Copyright © 2010 by the Society for Biology of Reproduction

10_1.indd Sek1:19

2010-03-26 11:17:45 Podstawowy czarny

20

Cryptorchidism

dism etiology. The appearance of antisperm antibodies can be considered as a marker or a serious side-effect of uncorrected cryptorchidism. If so, it could be implied that early surgery (orchidopexy) should be beneficial since it may prevent antisperm antibodies induction or at least eliminate them in the post-operative period. Reproductive Biology 2010 10 1: 19-35. Key words: cryptorchidism, antisperm antibodies, cryptorchidism treatment and diagnosis

INTRODUCTION - TESTICULAR DESCENT There have been controversies surrounding the precise definition of particular phases of testicular descent. Historically, two critical stages were proposed, around 12 to 16 weeks of gestation (testis descends the region of the inguinal ring) with temporary ‘re-ascent’ between 16 and 28 weeks of gestation due to an increase in the length and thickness of the gubernaculum [4]. More modern trends indicate at least 3 stages of descent in humans (for review see: [10]) while Polish authors indicate even 4-5 stages (for review see: [26]). From all the data available so far, we may agree on principal 3 stages: 1/ nephric displacement of the testis completed with the degeneration of the mesonephros (weeks of gestation: 7-8); 2/ transabdominal passage that includes movement of testis from the contact with the metanephros into the contact with the inguinal ring (completed at 21 weeks); 3/ inguinal passage or true descent that involves movement of testis from the peritoneal cavity into the lumen of processus vaginalis (28 weeks). There is a variety of factors including anatomical, genetic, endocrine and environmental which are associated with this process and which will be mentioned in the other subchapters of this review.

THE DIAGNOSIS The term cryptorchidism is derived from the Greek words “kryptos” meaning “hidden” and “orchis” meaning “testis”. Testicular descent into the cool

10_1.indd Sek1:20

2010-03-26 11:17:46 Podstawowy czarny

Kurpisz et al

21

(33ºC) environment of the scrotum is necessary to allow normal spermatogenesis. Testicular descent as proposed by Tomiyama et al. [23] is mainly controlled by Müllerian inhibiting substance (MIS), insulin-3-like hormone 3 (INSL3) and testosterone (T). Out of the monitored population of patients with cryptorchidism, 10-20% revealed bilateral undescended testes. It is estimated that at least 6% of these cases are due to an endocrine disorder [16]. Cryptorchidism is identified in 1-2% of males at 1 year of age [8]. Cryptorchidism (undescended testis, retentio testis or maldescended testis) is a condition where a testis which should normally be located at the bottom of the scrotum but instead appears in the abdominal cavity as a relatively frequent clinical symptom [28]. Cryptorchidism has once been proposed to be a part of “testicular dysgenesis syndrome” (TDS), which also includes hypospadiasis, reduced semen quality and testicular cancer [28]. Clinical examination involves visual description of the scrotum and palpation when the child is placed in supine, crossed-leg position and, if possible, in the upright standing position. Asymmetric or hypoplastic scrotum suggests unilateral and bilateral cryptorchidism, respectively [28]. Any undescended testis after the age of 6 months should be referred for orchidopexy. Cryptorchidism can occur as an isolated disorder in healthy boys, but it can be also a part of genetic or endocrine disorders, and/or somatic abnormalities [28].

DEVELOPMENT OF CRYPTORCHIDISM Genetic factors affecting testicular descent Regulation of prenatal testicular descent in humans is not fully understood, but numerous genetic and endocrine factors are involved [tab. 1; 28]. Normal testicular descent is dependent on the intact hypothalamus-pituitarytesticular axis. Malformations of the central nervous system and congenital hypogonadotropic hypogonadism may be associated with cryptorchidism [28]. Cryptorchidism with ambiguous genitalia always needs immediate systematic work-up. Insufficient androgen production or function will induce

10_1.indd Sek1:21

2010-03-26 11:17:46 Podstawowy czarny

22

Cryptorchidism

Table 1. Examples of factors that have been proposed to influence testicular

descent* Factors affecting transabdominal testicular descent Insulin-like hormone-3 (INSL3) Leucine-rich repeat-containing G protein-coupled receptor 8 (GREAT or RSFB2) Estrogens Factors affecting inguinoscrotal testicular descent Androgens Androgen receptor gene Gonadotropins Genital femoral nerve (GFN) Calcitonin gene related peptide (CGRP) Other factors affecting testicular descent Hoxa10 Anti-Müllerian hormone (AMN) AMN receptor gene *compilation of data reported in Ref. 25

undervirilization of the 46,XY male, due to deficiencies of the 5α-reductase, steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase/17-20 lyase or 17β-hydroxysteroid dehydrogenase and androgen receptor mutations causing androgen resistance. In the complete forms of Leydig cell hypoplasia or androgen resistance, the external genitalia are female, with testes located intra-abdominally or in the groin. The karyotype may vary, but frequently a 45,XO cell line can be found. Cryptorchidism and testicular dysgenesis or a development of streak gonads may also be seen in chromosome 9p deletion, campomoelic dysplasia (SOX9 mutation; sry-related HMG-box, high-mobility group) and mutations in the Wilms tumour (WT-1) or the sex determining region Y (SRY) genes. In a fenotypically newborn male with bilaterally nonpalpable testes, it is important to exclude a severely virilized genetic female, like in the case of congenital adrenal hyperplasia, placental aromatase deficiency or maternal hyperandrogenism [27, 28].

10_1.indd Sek1:22

2010-03-26 11:17:46 Podstawowy czarny

Kurpisz et al

23

The low frequency of mutations in insulin-like hormone 3 and leucinerich repeat-containing G protein-coupled receptors 8 (LGR8) genes in cryptorchid patients may be linked to the fact that in humans the first phase of testicular descent is seldom disrupted, i.e. the inguinoscrotal phase is usually affected. Furthermore, INSL3 may be important also in the second phase of testicular descent [27]. Hormonal factors affecting testicular descent Considerable risks of cryptorchidism include: a birth weight less than 2.5 kg, a size smaller than normal for a given gestational age and prematurity. Placental insufficiency with decreased human chorionic gonadotropin (hCG) secretion may be the sole underlying factor, as well as low maternal estrogen levels. Intra-uterine growth plays a key role in many male reproductive disorders [28]. Evidence is emerging that environmental factors may also play a role in increasing the risk of cryptorchidism in humans. Exposure to environmental factors, i.e. persistent organochlorines, phthalate monoesters and smoking, has recently been linked to adverse effects in infant reproductive development. Maternal diabetes, including gestational diabetes, also appears to be a risk factor for cryptorchidism [28]. In addition, it has been shown that, although basal plasma T level can be normal in cryptorchid boys, there is an insufficient increase of T after hCG stimulation when compared to normal response in approximately 30% of cryptorchid patients [29]. During the last 35 years, histological studies have contributed the most to our understanding of the etiology of cryptorchidism. Only histological examination accompanied by and sex hormone level assessment may exemplify hypogonadotropic hypogonadism in the majority of cryptorchid boys [9]. During pregnancy, hCG may replace the missing function of luteinizing hormone (LH) and this may explain why not all boys with hypogonadotropic hypogonadism are born cryptorchid. Pituitary gonadotropins may also have a role in keeping the testes in scrotal position, since hypogonadotropic hypogonadism may be associated with the ascent of the testes in infancy [27]. The observed associations between hypospadias and genetic abnormalities of sex chromosome number, androgen receptor function or testosterone path-

10_1.indd Sek1:23

2010-03-26 11:17:46 Podstawowy czarny

24

Cryptorchidism

ways provide evidence that the urethral defect occurs as a consequence of failed induction of the androgen-sensitive urethral plate. Ethnic/racial differences in maternal serum T during pregnancy may be also responsible for hypospadias. Other risk factors for hypospadias are: advanced maternal age, paternal risk factors such as a history of undescended testes and varicocoele, prematurity, low birth weight syndrome and monozygotic twin’s gestation [19]. Hypospadias and cryptorchidism have been linked with low-birth weight suggesting that fetal androgen dysfunction plays a role in the etiology of these conditions, although cryptorchidism can be resolved spontaneously especially in pre-term infants [1]. Testicular dysgenesis syndrome, especially hypospadias and cryptorchidism, is programmed by insufficient androgen function early in fetal life [25]. Environmental factors affecting testicular descent The relationship between cryptorchidism or hypospadias and environmental factors -xenoestrogens was examined. The results support the environmental working hypothesis for male sexual differentiation in humans. Since testis descendence is known to be dependent on a balanced steroid ratio (androgen:estrogen), therefore it is highly sensitive to disruption by exogenous estrogens [7, 24]. Xenoestrogens would provoke an imbalanced androgen:estrogen ratio, leading to an inadequate maturation of Sertoli and Leydig cells. Some authors, however, found no association between cryptorchidism and maternal exposure to xenoestrogens (or pesticides) during pregnancy [7]. Cryptorchidism can be associated with a specific haplotype of estrogen receptor alpha gene. It has been proposed that homozygosity for this haplotype would increase susceptibility to the effects of environmental endocrine disruptors of estrogenic origin [27].

CONSEQUENCES ON TESTICULAR FUNCTION According to the TDS concept, one could hypothesize that gonocytes that reach the testicular basement membrane and begin to differentiate into

10_1.indd Sek1:24

2010-03-26 11:17:46 Podstawowy czarny

Kurpisz et al

25

spermatogonia (before Sertoli cells suffered an insult) could be capable of maturing and differentiating in postnatal life, resulting in semiferous tubules containing germ cells. On the other hand, intraluminal gonocytes could be incapable of interacting with the disrupted Sertoli cells, thus preventing their migration to the basal lamina and resulting in apoptosis thus, leading to the development of Sertoli cell only syndrome [18]. Cryptorchidism may have the long-term consequences on testicular function, including disturbed spermatogenesis and risk of testicular cancer, even after successful treatment [24]. Most previous studies on semen quality have used the WHO criteria of 20×106 spermatozoa/ml as the lowest normal sperm concentration. Adult men with persistent bilateral cryptorchidism have usually azoospermia, whereas after operation 28% of such males had a normal sperm count. Approximately 49% of men with persistent unilateral cryptorchidism revealed normal sperm concentration as compared to 71% after orchidopexy. Few studies have assessed semen quality in relation to age at performed orchidopexy. Surgery between 10 months and 4 years of age in bilateral cryptorchidism led to a normal sperm count in 76% of the cases, compared to 26% when the surgery was performed between 4 and 14 years. In unilateral cryptorchidism this impact of timing was not as obvious: 75% vs. 71% if operated between 10 months to 6 years vs. group of 9-12 years, respectively. It is unknown yet whether current guidelines of earlier orchidopexy would further improve such outcome [28]. Maturation of germ cells starts with differentiation of gonocytes into spermatogonia, and is usually completed by the age of 6 months. At the age of 3 months, dark (Ad) spermatogonia start to appear and steadily increase in number. This number is reduced in the testes of cryptorchid boys, indicating that there is a failure in the maturation process of the gametogenic cells. This reduction (in spermatogonia) is more severe than the reduction in the number of total germ cells. Disproportionate reduction in Ad spermatogonia correlates directly to future spermiograms and represents the fundamental abnormality in germ cell development in cryptorchidism [29]. Sperm DNA damage is significantly increased in men with idiopathic oligozoospermia and in cryptorchid subjects. The finding of increased reactive oxygen species (ROS) levels in infertile subjects may indicate that oxi-

10_1.indd Sek1:25

2010-03-26 11:17:46 Podstawowy czarny

26

Cryptorchidism

dative stress is involved in the pathogenesis of sperm DNA damage in these individuals [21]. High ROS level disrupts the inner and outer mitochondrial membranes, inducing the release of the cytochrome-c protein and activating the apoptosis (it augments DNA fragmentation of abnormal spermatozoa; [2]). Sperm density is variable in both the unilateral and bilateral cryptorchid males. However important semen morphology, density and motility may appear, natural fatherhood is the gold standard to assess the fertility of the cryptorchid male. Thus, bilateral cryptorchidism provoked significant delays in conceiving as opposed to unilateral cryptorchid patients who impregnated their partners similarly to normal controls [16].

RECOMMENDED TREATMENT The optimal treatment regimen for cryptorchidism remains unknown [28]. However, systematic follow-up of patients into adulthood has been observed. Surgery is currently recommended for congenital cryptorchidism in early infancy to avoid secondary degeneration of the testis, which is believed to be caused by the elevated temperature of the nonscrotal gonad(s) [5]. A higher temperature in experimental cryptorchid testes in rats has been found to cause high production of ROS as a result of a reduction of superoxide dismutase (SOD) activity in the testicular tissue. The increased ROS level in the cryptorchid testis is also an important risk factor for the occurrence and development of testicular tumors [12]. The effects of hormonal therapy on the contralateral (descended testis) have been sporadically studied, the Ad/T [number of adult dark (Ad) spermatogenic per tubule (T)] was significantly higher in the hormonally treated boys. It was shown that the differentiation of gonocytes into Ad spermatogonia is a testosterone-dependent process. If an adequate increase in plasma T follows hormonal stimulation (hCG), normal germ-cell maturation occurs [29]. Although the treatment is mostly a surgical one, there are some reports on several cases of testis migration after hormonal treatment with hCG or gonadotropin releasing hormone (GnRH). A hypothesis that could explain

10_1.indd Sek1:26

2010-03-26 11:17:46 Podstawowy czarny

Kurpisz et al

27

the migration of the testicle after using hCG would be the increase of T level inducing the appearance of androgen receptors on fibroblasts of the gubernaculums. This would degrade the extracellular matrix and stimulate the contraction of the muscle fibers in the gubernaculums, thus determining their shortening [6]. Furthermore, successfully (surgically) treated patients are still at risk of infertility, but after 6 months of luteinizing hormone-releasing hormone analogue (LHRHa) treatment a long lasting increase in the number of germ cells in their cryptorchid testis was observed. Recognizing that the endocrinopathy at mini-puberty is responsible for ensuring infertility in cryptorchidism, hormonal treatment should be implemented in cryptorchid boys having early successful orchidopexy but still being at risk of infertility [9]. The undescended testis and the effect of orchidopexy on male fertility are far from clear-cut. What effect orchidopexy may have on these patients’ fertility in the long term is complicated by numerous other factors. The issues are: 1/ the age at surgery, 2/ bilateral vs. unilateral cryptorchidism, 3/ the preoperative testicular size, 4/ suture placement and/or testis biopsy, 5/ the accuracy of semen analysis, and 6/ the partner prospective fertility. What effect does the fixation of the unilateral cryptorchid testis on the contralateral testis poses another question. A number of statements are frequently presented as trivial as “higher testis is always worse”, “earlier surgery is better than later” and “bilateral cryptorchidism is worse than unilateral” [16]. If hormonal changes are the reason for cryptorchidism, then the logic implies that hormonal therapy will both: 1/ induce testicular descent, and 2/ increase the number of germ cells as well as improve fertility [16]. The recommended age for orchidopexy has steadily fallen over the decades with the evolved understanding of spermatogenesis and improvement in surgical techniques. It is generally assumed that spontaneous descent no longer occurs after approximately 3 months of age in a term baby, and is rare beyond 6 months of age (there was a decrease in the germ cells number in those individuals who underwent surgery after 6 months as compared to those with surgery at less than 6 months; there was no statistical difference,

10_1.indd Sek1:27

2010-03-26 11:17:46 Podstawowy czarny

28

Cryptorchidism

however, in the sperm counts between these two groups 20 years later). Ludwig and Potempa in 1975 [14] demonstrated 90% of fertility in those individuals who were operated within the first 2 years of life as opposed to 50% for those who were operated between 9 and 12 years of age. If surgery was delayed beyond 12 years of age, there was noted a significant decrease in fertility in this group [16]. There is no evidence that early surgery (for cryptorchidism) decreases the incidence of testicular cancer [17]. Orchidopexy for bilateral cryptorchidism leads to a higher sperm count if surgery is performed before 3 years of age as compared to surgery after 4 years of age. Also, the ratio (in sperm count) between the retained testis and its scrotal counterpart showed a significant increase following early surgery, while in the late treated group this ratio showed a significant decrease after surgery. These results strongly suggest that surgery at the age of 9 months rather than after the age of 3 years is beneficial for proper testicular development [13].

AUTOIMMUNE BACKGROUND Studies on testicular autoimmunity are important for a better understanding of human male infertility since it has been suggested that there are some immunologically-mediated infertile patients among many idiopathic male infertile patients. There are data indicating that unilateral testicular injury induces a delayed type hypersensitivity (DTH) response to autologous testicular cells and later indeed induces the contralateral autoimmune orchitis [20]. Antisperm autoimmunity, namely its cellmediated form, also appears to play a significant role in the impairment of spermatogenesis [15]. Steroid hormones and male immune system Steroid sex hormones and GnRH are important factors which modulate the immune system (tabs. 2 and 3; [22]). Data suggest that GnRH may play an important role in B-cell immunity. Researchers have been unable to docu-

10_1.indd Sek1:28

2010-03-26 11:17:46 Podstawowy czarny

Kurpisz et al

29

Table 2. Summary of experimental data showing the effects of GnRH on the immune system* Expression of GnRH and GnRH-R Both are expressed in primary lymhoid organs and peripheral immune cells including human lymphocytes Immune system development Involved in immune system development (no data in humans) Immune effects Potent immune-stimulating action; increases the levels of interleukin-2, interferon-γ, T-helper cells Impact on autoimmunity Potential to exacerbate autoimmune disease; effect independent from gonadal steroids Sexually dimorphic immune response Different expression of GnRH and/or G proteins in males and females *compilation of data reported in Ref. 20

ment an effect of androgens on serum IgG level regardless of the GnRH presence. Testosterone, 5α-dihydrotestosterone, as well as dehydroepiandrosterone (DHEA) have been equally ineffective in reducing serum IgG level. On the other hand, T administration clearly suppressed B-cell proliferation in GnRH-sufficient mice [11]. Much information is available showing that sex steroids such as T and 17β-estradiol (E2) are critically involved in the control of sexual dimorphism and the immune response. Like other steroids, T and E2 exert their major long-term effects on cell growth, differentiation, and functions through intracellular androgen receptors (iAR) and estrogen receptors [(iER)α and (iER)β], respectively, belonging to the nuclear receptor superfamily. The iAR and iER are ligand-inducible transcription factors causing activation or repression of genes. The expression of iAR and iERα suggests direct responsiveness of B-cells to T and E2. Information is available that both

10_1.indd Sek1:29

2010-03-26 11:17:46 Podstawowy czarny

30

Cryptorchidism

Table 3. Summary of experimental data showing the effects of sex steroids on the immune system* Expression of steroid receptors Estrogen (ER) and androgen (AR) receptors are expressed in all immune cell subsets, except AR in mature B and T-cells Thymus and bone marrow effects Testosterone: thymic atrophy, thymocyte apoptosis and B-cell precursor depletion in bone marrow Estrogen: same as testosterone, but on different immune subsets Peripheral T- and B-cells Testosterone: enhances suppressor T-cells and diminishes B-cell number Estrogen: enhances helper T-cells and increases autoantibody production Impact on autoimmunity Androgens: seem to have suppressor activity Estrogens: seem to have stimulating activity Sexually dimorphic immune response Impact is better expressed during development of immune response; mechanism is unclear *compilation of data reported in Ref. 20

T and E2 influence the production of immunoglobulin levels. For instance, T has been shown to inhibit IgM and IgG production by B-cells, while E2 enhances immunoglobulin production. It appears likely that sex hormones influence B-cells at an early stage of development, also acting as negative regulators of B cell-lymphopoiesis [3]. Own experience Our recently obtained but unpublished data from hormonal investigations indicated that the levels of LH, follicle-stimulating hormone (FSH) and T in patients with cryptorchidism (age 5-9; n=126 and 10-14 years; n=121) were not significantly decreased compared to healthy controls. Young patients

10_1.indd Sek1:30

2010-03-26 11:17:46 Podstawowy czarny

Kurpisz et al

31

with cryptorchidism (groups of age 0-1; n=7 and 1-4 years; n=81) had also normal levels of sex hormones. Data obtained so far showed that in all groups of surgically treated patients (with cryptorchidism) antisperm antibodies (AsA) were detected. However, it should be noted that not all AsA families may exert equal pathognomic values. For example, bound-to-head AsA clearly revealed its statistically significant potential discriminating group with cryptorchidism vs. healthy controls while AsA directed to the tail tip did not (tab. 4). It is interesting that in our young cohorts (groups of 0-1 and 1-4 years of age) the performed orchidopexy resulted in rapidly decreasing antisperm antibodies levels but in age groups 5-9 and 10-14, the high levels of antisperm autoantibodies had a long-term impact. Table 4. Comparison of antisperm antibody (AsA) levels and their isotypes obtained from sera of prepubertal boys with cryptorchidism and healthy controls by immunobead test* Cryptorchidism N=60 AsA topography head neck principal piece tail tip IgA IgG IgM

mean±SD

Healthy individuals N=23

Positive individuals

mean±SD

7.93±20.50 0.62± 2.00 3.10± 8.10

n 11 7 11

% 18 12 18

26.71±41.90

22

0.78±1.71 0.13±0.50 0.82±1.70

15 4 15

26 25.74±43.35 Ig class 25 0.13±0.34 7 0.00±0.00 25 0.17±0.39

0.00±0.00 0.00±0.00 0.91± 2.01

Level of Positive significance individuals (p) n % 0 0 0.030 0 0 0.182 4 17 1.000 6

26

0.442

3 0 4

13 0 17

0.373 0.572 0.568

* analyzed pre-pubertal individuals were classified to Tanner stage I and II; SD: standard deviation; N: number of cases analyzed in groups under study; n: number of positive cases for AsA; Statistical differences were obtained by using Mann-Whitney U test

10_1.indd Sek1:31

2010-03-26 11:17:46 Podstawowy czarny

32

Cryptorchidism

FINAL REMARKS The following associations between cryptorchidism and infertility have been found: A. Differentiation of gonocytes (that reach the testicular basement membrane) into spermatogonia is hormonally dependent. In cryptorchid boys, however, the number of gonocytes is reduced, so it is unclear whether differentiation failure takes place in the process of germ cells development. Disproportionate reduction in Ad spermatogonia represents the fundamental abnormality in germ cell development in cryptorchidism (theoretically in healthy boys adult dark spermatogonia increase in number at the age of 3 months, transformation of gonocytes into spermatogonia takes place at age of 6 months). Differentiation of gonocytes into dark spermatogonia is a testosterone-dependent process. The published data show that in patients with cryptorchidism the levels of T and gonadotropins is low, while increased plasma T can inhibit IgM and IgG-production by B-cells and is a negative regulator of B-lymphopoiesis. It can be implied that decreased levels of T, FSH and LH may explain why production of antisperm autoantibody begins. B. Apoptosis of germ cells. a/ Sperm DNA damage is significantly increased in males with cryptorchidism (higher temperature in cryptorchid testis upregulates ROS levels and affects seminal redox balance - such can be a pathogenesis of sperm DNA damage in these patients). b/ As well as in the patient with cryptorchidism it was demonstrated that in the hypogonadotropic hypogonadism an unbalanced ratio androgen:estrogen or low hCG (during fetal life) may be prerequisite to apoptosis of germ cells (this can be a preliminary step towards the autoimmune reaction!). c/ Autoreactive B-cells can be rescued from negative selection by antiapoptotic molecules (Bcl-xL). Testosterone may promote the survival and activation of high affinity autoreactive B-cells [in systemic lupus erythematosus (SLE) the higher affinity B-cells may not be only a source of pathogenic autoantibody, but may also exclude low affinity autoreactive B-cells, thus facilitating the clearance of apoptotic debris]. It was found that the decreased levels of T, FSH and LH observed in some cases can explain why the abnormalities in apoptosis are triggered.

10_1.indd Sek1:32

2010-03-26 11:17:46 Podstawowy czarny

Kurpisz et al

33

C. Endocrine mediators (cortisol, estrogen, testosterone etc.) may affect antigen presenting cells (APC) differentiation and function. Normally, APC are involved in the antigen degradation and presentation. It was demonstrated that the surgical treatment of cryptorchidism is successful, although in the absence of the hormonal therapy the low levels of T, FSH and LH in these patients remain. Normally GnRH shows a potential to exacerbate an autoimmune disease, while T suppresses the autoantibody production and diminishes B cell number. It was found in some patients with cryptorchidism that decreased levels of T and gonadotropins can be associated with the development of autoreactive immune response. D. Early successful orchidopexy still presents a risk of infertility, although a very little immune autoreactivity in patients from groups of 0-1 and 1-4 years of age was found. It can be hypothesized that the immune system at this age has little capacity for antibody production.

REFERENCES 1. Abdullah NA, Pearce MS, Parker L, Wilkinson JR, McNally RJ 2007 Evidence of an environmental contribution to the aetiology of cryptorchidism and hypospadias? European Journal of Epidemiology 22 615-620. 2. Agarwal A, Makker K, Sharma R 2008 Clinical relevance of oxidative stress in male factor infertility: an update. American Journal of Reproductive Immunology 59 2-11. 3. Benten WP, Stephan C, Wunderlich F 2002 B cells express intracellular but not surface receptors for testosterone and estradiol. Steroids 67 647-654. 4. Bramann F 1884 Contribution to the science on testicular descent and gubernaculum formation in humans. (in German) Archiv für Anatomie und Entwicklungsgeschichte 310-340. 5. Davanc M, Kibar Y, Irkilata HC, Demir E, Tahmaz L, Peker AF 2007 Long-term outcome of scrotal incision orchiopexy for undescended testis. Urology 70 786-788. 6. El Zoghbi CS, Favorito LA, Costa WS, Sampaio FJ 2007 Structural analysis of gubernaculum testis in cryptorchid patients submitted to treatment with human chorionic gonadotrophin. International Brazilian Journal of Urology 33 223-230. 7. Fernandez MF, Olmos B, Granada A, Lopez-Espinosa MJ, Molina-Molina JM, Fernandez JM, Cruz M, Olea-Serrano F, Olea N 2007 Human exposure to endocrine-disrupting chemicals and prenatal risk factors for cryptorchidism and hypospadias: a nested casecontrol study. Environmental Health Perspectives 115 Suppl.1:8-14. 8. Gatti JM, Ostlie DJ 2007 The use of laparoscopy in the management of nonpalpable undescended testes. Current Opinion in Pediatrics 19 349-353.

10_1.indd Sek1:33

2010-03-26 11:17:46 Podstawowy czarny

34

Cryptorchidism

9. Hadziselmovic F, Zivkovic D 2007 Is the prohibition of hormonal treatment for cryptorchidism, as suggested by Nordic consensus group, justifiable? Acta Paediatrica 96 1368-1379. 10. Heyns CF, Hutson JM 1995 Historical review of theories on testicular descent. Journal of Urology 153 754-767. 11. Jacobson JD, Ansari MA 2004 Immunomodulatory actions of gonadal steroids may be mediated by gonadotropin-releasing hormone. Endocrinology 145 330-336 12. Kawakami E, Hirano T, Hori T, Tsutsui T 2007 Testicular superoxide dismutase activity, heat shock protein 70 concentration and blood plasma inhibin alpha concentration of dogs with a Sertoli cell tumor in a unilateral cryptorchid testis. Journal of Veterinary Medical Sciences 69 1259-1262. 13. Kollin C, Karpe B, Hesser U, Granholm T, Ritzen EM 2007 Surgical treatment of unilaterally undescended testes: testicular growth after randomization to orchiopexy at age 9 months or 3 years. Journal of Urology 178 1589-1593. 14. Ludwig G, Potempa J 1975 Optimal time for treating cryptochism. (In German) Deutsche Medizinische Wochenschrift 100 680-683. 15. Madar J, Urbanek V, Chaloupkova A, Nouza K, Kinsky R 2002 Role of sperm antibodies and cellular autoimmunity to sperm in the pathogenesis of male infertility. (In Czech) Ceska Gynekologie 67 3-7. 16. Murphy F, Paran TS, Puri P 2007 Orchidopexy and its impact on fertility. Pediatric Surgery International 23 625-632. 17. Myrup C, Schnack TH, Wohlfahrt J 2007 Correction of cryptorchidism and testicular cancer. New England Journal of Medicine 357 825-827. 18. Nistal M, Paniagua R, Riestra ML, Reyes-Mugica M, Cajaiba MM 2007 Bilateral prepubertal testicular biopsies predict significance of cryptorchidism-associated mixed testicular atrophy, and allow assessment of fertility. American Journal of Surgical Pathology 31 1269-1275. 19. Pohl HG, Joyce GF, Wise M, Cilento BG Jr 2007 Cryptorchidism and hypospadias. Journal of Urology 177 1646-1651. 20. Sakamoto Y, Matsumoto T, Kumazawa J 1998 Cell-mediated autoimmune response to testis induced by bilateral testicular injury can be suppressed by cyclosporin A. Journal of Urology 159 1735-1740. 21. Smith R, Kaune H, Parodi D, Madariaga M, Morales I, Rios R, Castro A 2007 Extent of sperm DNA damage in spermatozoa from men examined for infertility. Relationship with oxidative stress. (In Spanish) Revista Medica de Chile 135 279-286. 22. Tanriverdi F, Silveira LF, MacColl GS, Bouloux PM 2003 The hypothalamic-pituitarygonadal axis: immune function and autoimmunity. Journal of Endocrinology 176 293304. 23. Tomiyama H, Sasaki Y, Huynh J, Yong E, Ting A, Hutson JM 2005 Testicular descent, cryptochidism and inguinal hernia: the Melbourne perspective. Journal of Pediatrics Urology 1 11-25. 24. Wang F, Roberts SM, Butfiloski EJ, Sobel ES 2007 Acceleration of autoimmunity by organochlorine pesticides: a comparison of splenic B-cell effects of chlordecone and estradiol in (NZBxNZW) F1 mice. Toxicological Sciences 99 141-152.

10_1.indd Sek1:34

2010-03-26 11:17:46 Podstawowy czarny

Kurpisz et al

35

25. Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, Sharpe RM 2008 Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. Journal of Clinical Investigation 118 1479-1490. 26. Woźniak W, Bruska M 1998 Testicular descent in humans. (In Polish) In Andrologia, pp 23-26. Eds Semczuk M, Kurpisz M. PZWL, Warszawa. 27. Virtanen HE, Toppari J 2008 Epimiology and pathogenesis of cryptorchidism. Human Reproductive Update 14 49-58. 28. Virtanen HE, Bierknes R, Cortes D, Jorgensen N, Rajpert-De Meyts E, Thorsson AV, Thorup J, Main KM 2007 Cryptorchidism: classification, prevalence and long-term consequences. Acta Paediatrica 96 611-616. 29. Zivkovic D, Bica DT, Hadziselmovic F 2007 Relationship between adult dark spermatogonia and secretory capacity of Leydig cells in cryptorchidism. BJU International 100 1147-1149.

10_1.indd Sek1:35

2010-03-26 11:17:46 Podstawowy czarny