This essay discusses the cryptorchidism, giving the complex analysis of the causes, epidemiology, complications, consequences, diagnoses and treatment for the undescended testicles disorder. The term cryptorchidism refers to the male urogenital disorder, where both or one testicle fails to move into the scrotum after birth, or, in some cases, is absent. According to Steven G. Docimo, during the embryonic life the testis differentiates adjacent to mesonephric kidneys and normally descends via the inguinal canal to the scrotal position. Generally, the mechanism that regulates prenatal testicular descent stayed understudied and obscured in some parts to medical community, yet there is persuasive evidence that endocrine, genetic, and environmental factors are involved, approximately 1-2% of males are diagnosed with undescended testicle. In majority of cases the testicle is palpable, however around 20% of patients have nonpalpable form of disorder.
According to Peter F. Lawrence, Richard M. Bell & Merril T. Dayton (2007), cryptorchidism (from the Greek "hidden testicle") is a disorder in which the testicles (one or both) do not move to the usual position in the scrotum but stay in the inguinal or inside the lower abdomen where they are formed.
Lewis B. Holmes (2011) suggests more specific definition of the disorder, where the testis is considered undescended when it cannot be placed down and kept without tension at a distance of 4 centimeters below the symphysis pubis in the term male infant or 2,5 centimeters in the prematurely born newborns.
Testicular descent from abdomen to scrotum involves two distinct phases of the trans-abdominal movement and the inguino-scrotal descent. As usual, only one testis fails to move into the scrotum whereas the other fulfills the normal male sexuality function. Nonetheless, there are cases where infants are born with both testicles situated in the abdominal civility or inguinal channel. This dysfunction is more serious as undescened testes usually produce insufficient amount of sperm or are nonfunctional at all which means infertility (Carlo Foresta, Daniela Zuccarello, Andrea Garolla, and Alberto Ferlin (2008)). Moreover, the research of Carlo Foresta (2008) suggests that undescended testes contribute to the risk of testicular cancer in adulthood.
The male testes begin to develop approximately in forty days after impregnation. They are formed inside the fetal abdomen. Normally, the testes travel through the inguinal canal and abdomen near the end of eights month. A few days before birth, the testes acquire their regular position into the bottom of the scrotum. The transabdominal phase occurs between tenth and twenty-third weak of human embryos development. Subsequently, the inguino-scrotal stage occurs between twenty-sixth week and birth.
According to Ora H. Pescovitz & Erica A. Eugster (2004), the clinical features of cryptorchidism include intra-abdominal or inguinal (rarely ectopic) positional of testes, which are often isolated but may well be accompanied by underlying syndromes or genitourinary defects. The disorder contributes to a hazard of development of testicular germ cell tumor, particularly, the intersex states with y-chromosome may develop gonadoblastoma and seminoma.
Whereas cryptorchidism was commonly classified as congenital disorder, the latest UK studies of Acerini (2009) for the first time recorded and described acquired type of cryptorchidism or "ascending testis". The study detected the cases with acquired form of disorder assessing testicular position at birth time, and at the age of 3, 12, 18 and 24 months. The results showed that the prevalence of cryptorchidism declined from 5,6% at birth time to 2.4% at 3 months, but surprisingly increased again to 6.7% at 12 and 7,0% at 24months as a result of new cases. The results also suggested that newborns in these acquired cryptorchidism cases had shorter penile length during infancy than other infants. The researchers suggested the explanation for this fact in a reduced early postnatal activity.
Epidemiology and incidence
The Carlo Foresta (2008) suggests that the frequency of cryptorchidism disorder cases may vary among different countries, though the generally accepted rate is 2-4% in full-term male births. The epidemiological studies in case of cryptorchidism may be affected by the fact that there is no uniform definition for the disease. For instance, some studies in Denmark recorded high prevalence of cryptorchidism at a rate of 9% using the definition that includes high scrotal position of testes, which contributed to 7% out of 9%, as cryptorchidism. On the other hand, another study suggested the frequency of 2,4%, using the definition which does not include high scrotal testes position to cryptorchidism disorder (Carlo Foresta (2008)). Moreover, approximately 50% of cryptorchid testicles at birth may descend without outside interference during the three first months after birth, thus the frequency of real disorder drops to 1-2% for the 1-year-old males (M. William Schwartz (2003). Lewis B. Holmes (2011) suggests that the factors that contribute to the prevalence of cryptorchidism include low birth weight, prematurity and small size for gestational age. For example, up tp 20-25% of the infants with a weight less than 2,5 kilograms suffer from cryptorchidism. In addition, according to Carlo Foresta, Daniela Zuccarello, Andrea Garolla, and Alberto Ferlin (2008), the differences in cryptorchidism incidents rate are recorded in distinct geographical areas. Thus, the studies from England and Denmark recorded the substantial increase in prevalence of cryptorchidism for males of at least 2,5 kilograms in weight. The possible causes for such increase may include negative changes in environment that disrupt testicular descent. Contrary to this, Italy recorded the decrease of cryptorchidism from 4,3% in 1978 to 2,7% in 1997.
In addition, Lewis B. Holmes (2011) suggests that the higher prevalence of cryptorchidism is detected among twins than singletons, but these observations also correlate with the fact that the rate of disorder is higher in low birth weight infants whereas prematurity and low birth weight are higher among twins.
According to Ora H. Pescovitz & Erica A. Eugster, (2004), the associated with cryptorchidism malformations include inguinal hernia, genitourinary anomalies, malformations of kidney and urethra, and anomalities of vertebrae. Inguinal hernia is the most common complication as the processus vaginalis persists until the testis has reached its point of full descent. The persisting processus becomes a route for inguinal hernia. The associated genitourinary malformations may include hospadias, hypoplasia of the penis or bifid scrotum. Moreover, in some cases the patients have malformations of kidney and urethra on the side of undescended testicle.
According to Lawrence S. Neinstein (2008), testicular examination should be conducted by a professional, using two-handed palpation technique, in warm and anxiety-free atmosphere as uncomfortable surrounding could cause the cremasterix reflex to retract the testicle. In the cases, where testicles are non-palpable, the sonography with a tranducer of high resolution may provide a correct picture with accuracy of 84%. This imaging technique allows assessing the size and parenchymal structure of the inguinal testicles. To detect the intraabdominal position of the testicle, MRI is considered a useful tool with correct classification of 85%. The location of non-palpable testicle is usually defined by laparoscopy. Generally, there is no need for performing laboratory tests, though pediatric endocrinological assessment may be used to detect other syndromes such as testosterone-producing testicular tissue or anorchia.
Treatment and therapy
According to Michael J. Mathers (2008), the treatment of cryptorchidism may be hormonal, surgical, or a combined. To ensure the success, the treatment of undescended testiscles in infants is recommended start after six months and completed before the child is of one year old. In many cases, the best initial treatment mode is hormone therapy. The unsuccessful cases in hormonal therapy should be immediately preceded to surgery. Generally, the positive results of the treatment depend on the initial position of the testes.
The hormonal therapy includes the application of human chorionic gonadotropin (hCG) that stimulates the testicle to produce testosterone and the use of gonadotropin releasing hormone (GnRH). The success rate hCG hormonal treatment varies between 20% and 99% in different controlled studies, whereas the success rate of GnRH therapy also varies greatly between 0% and 78%). Nonetheless, there also negative effects of the hormonal treatment. For instance, the drawbacks of hCG therapy may include the penis enlargement, recorded in 3% of patients, the enlargement of testicles, the early genital hair growth, and even the facts of the change of children's behavior toward aggressive during the treatment (Michael J. Mathers, Herbert Sperling, Herbert Rubben, Stephan Roth (2009). In addition, E Martin Ritze'n (2008) suggests that hCG treatment may appear harmful to spermatogenesis as germ cells may show increased apoptosis. The postoperative hormone therapy such as low dose of GnRH analogs may be beneficial for the fertility in adulthood, though an individual approach and careful considerations should be applied.
According to M. William Schwartz (2003), in the cases, where hormonal therapy is inappropriate, it is important that surgery be performed before the child's first birthday. If the testicles are in intra-abdominal position, both open surgical and laptoscopy can be used as equivalent techniques. In other cases, the prevailing method is orchiopexy. Ora H. Pescovitz and Erica A. Eugster (2004) describe the process of surgical treatment for palpable and non-palpable testes. Most palbable cryptorchid testes can be operated through inguinal orchiopexy. The surge makes and inquisition to the lower abdominal skin crease over the expected location of the inguinal canal. The roof of the inguinal canal is opened in the direction of its fibers and the spermatic cord is freed approximately to the level of internal inguinal ring. Further, the processus vaginalis is separated from the anteromedial aspect of the spermatic cord and ligated at the level of the internal inguinal ring. Finally, the subcutaneous dartos pouch is made in the scrotal wall and the testicle is transferred into the dependent scrotum.
In nonpalpable cases, the surgery intends to determine if the testicles are (or is) present and then, if one is identified, either to move it to scrotum or to remove it. According to Sam D. Graham, Thomas E. Keane (2009) the testicle is evaluated for size and location. If it appears to be atrophic or glossly abnormal, then orchiectomy shoud be considered. If the testicle is assessed as relatively normal, then the surge evaluated the ability to mobilize it toward the scrotum based on the distance of the testicle to internal inguinal ring and redundancy of the spermatic vessels. Sam D. Graham, Thomas E. Keane (2009) believe that the testis may be delivered to the scrotum in the most safe and effective way by using the 2- or 3mm instruments and a radially dilating trocar system. Using laporoscopy, the surge accesses abdomen by inserting a port through an infraumbilical site. Laporoscopy includes following stages: establishing a peritoneal pedicle fleap, creating a neo-inguinal hiatus and testicular delivery into the scrotum.Further is it is important to gain additional cord lengths and secure the testicle. Final stage is closure and exiting the abdomen. Generally, laporoscopy is complicated operation and should be performed very carefully. According to Ora H. Pescovitz and Erica A. Eugster (2004), even after the orchiopexy fertility is impaired in 50% to 70% of males with unilateral form of disorder and 75% of bilateral cryptorchidism type. The question of the early orchiopexy effect on fertility function is still under research, though, it is a fact that males with both undescended testes are infertile in adulthood unless they received a treatment.
The two common groups of cryptorchidism disorder include genetic factors and environmental factors. According to Lewis B. Holmes (2011), in 5% of the 110 cryptorchidism patients chromosome abnormalities were detected. In addition, the studies showed that cryptorchidism disorder is familial. In two studies the frequency of undescended testes among brothers was recorded up to 6,5% and up to 3,7% among fathers. Recently, the studies revealed that hormones play crucial role in testicular descent. The two phases of testes descent are regulated in distinct ways, thus transabdominal stage depends on insulin-like factor 3 (INSL3) whereas inguinoscrotal phase is significantly dependent on androgen hormones. The anti-Mullerian hormone and testosterone are also important in two-stage process of testes' descends. Aside from the role of hormones, there appears to be a very significant influence of calcitonin gene-related peptide and genitofemoral nerve. The discovery of INSL3 as the important hormonal regulator of the gubernacular differentiation and further studies are of extreme significance as they provided evidence that the disruptions of the INS3 pathway can lead to testicular maldescent. Thus, the disruptions of androgen receptor function, in estrogen receptor L gene, and INS3 gene are genetic factors that contribute to the occurrence of cryptorchidism in male infants.
According to Carlo Foresta, Daniela Zuccarello, Andrea Garolla, and Alberto Ferlin (2008), the increased incidence of cryptorchidism in the last years is often considered a consequence for the environmental factors playing a role of endocrine disruptors of testicular descent. The environmental endocrine disruptors include industrial chemicals, synthetic and natural hormones, phytoestrogenes and mycoestrogenes. The environmental compounds alter the action of hormones that are responsible for normal testicular descent. For instance, the exposure to pesticides may create anti-androgenic and estrogenic effects contributing to the formation of the disorder in fetus. One of the most serious endocrine disruptors is organohalogen pollutants, which a accumulated in the products and are consumed through the animal origin food. Another endocrine disruptor is phthalates, which is used in industrial processes and is one of the detrimental environmental contaminators. Among the other endocrine disruptors are herbicides, fungicides and industrial chemicals like bisphenol A. According to the by Skakkebaek's thory, TDS, the cryptorchidism may be caused by the combination of genetic and environmental factors. Some studies provided the insights, that INS3 plays vital role in testicles descent, though the clear mechanism of the action of estrogens regulating fetal Leydig cell Insl3 transcription is still unclear. Thus, it turns that any antiandrogenicor estrogenic substance may have negative effects on testicular descent. In addition, it is important that one understand the possible synergies between several different low-dose xenobiotic constituents, where even low levels of environmental estrogens may be responsible for genereting an unfavourable effects if androgen production is also reduced by antiandrogens.
Consequences of chryptorchidism
According to Carlo Foresta (2008), the consequences of cryptorchidism may vary though there are two main results of the disorder such as infertility and testicular cancer.
Cryptorchidism belongs to heterogeneous disorders, and the function of testes may be altered in adulthood to different extents withranging seminal quality from normozoospermia to complete azoospermia. The alteration of spermatogenesis in the cases of cryptorchidism contributes to men's subfertility in adulthood, where bilateral forms of disorder tend to suffer more than unilateral. In many cases, excryptorchid examples provide reduced sperm concentration, high level of FSH and decreased inhibin B plasma levels that contribute to decrease in testicular volume and subsequent decline of fertility potential. The studies reported an abnormal sperm count in approximately 50% of unilateral and in up to 80% of bilateral cases. The studies have also shown the positive correlation between the age cryptorchid boys are at surgery and the sperm concentration that may possibly mean that the younger is a child when it gets surgery help, the less chance of infertility may occur in adulthood. Generally, 20% of all azoospermic cases occur due to cryptorchidism, whereas one third of cryptorchidism patients are infertile in spite of the treatment and surgery measures.
Another possible consequence of undescended testicles is the cancer. Even though the cause of testicular cancer stays blurred, a sound association with cryptorchidism is popular among medical practitioners. It is a fact that disordered males are exposed to higher risk of testicular cancer, whereas the risk of testicular neoplasm, constituting 2-3% , is four times higher than an average for the society. However, the statistical findings have not found the medical explanation yet. Whereas much evidence proves the genetic role in both cryptorchidism and testicular cancer, no research results suggesting the genetic link between two diseases were reported (Carlo Foresta (2008)). In recent years, two theories were suggested to explain the correlation between cryptorchidism and testicular cancer. The TDS hypothesis, which is considered to be widely accepted, suggests the link between genetic factors, failures of endocrine system, and the consequent development of cryptorchidism, hypospadias, infertility and testicular cancer. This relation may be explained by the fact that disturbed gonadal development in which altered gonocytes cannot differentiate in normal way and increasingly degenerate up to carcinoma in situ, which lead to germ cell tumor and invasive progression, resulting in testicular cancer. The supporting evidence for the TDS hypothesis is that the increased rate of cryptorchidism has paralleled the increased incidents in testicular cancer and male infertility. Generally, the theory is based on common cause of testis neoplasia and cryptorchidism, whereas the second hypothesis suggests a cause-and-effect relationship between undescended testes and testicular cancer. The supporting evidence for this theory lies in surgery statistics, where the surgical intervention in early years show reduced rates of testicular cancer in adulthood. Nonetheless, the surgery of cryptorchidism does not completely takes out the risk or testicular cancer (Carlo Foresta (2008)).
Finally, the studies of Henrik M0LLER and Niels Erik (1996) revealed that cryptorchidism might be a reason for late puberty. Moreover, the detailed analysis recorded that this relationship was stronger in men with bilateral than with unilateral form of disorder. Additionally the association was also stronger in men who received cryptorchidism treatment after the age of ten years than in category who had been treated before reaching the age of ten years. Thus, it appears that puberty age may be delayed due to impaired hormonal function of the undescended testes.
To sum up, the essay explains the cryptorchidism disorder, a male congenital or acquired pathology where one (unilateral form) or both testicles (bilateral form) fail to move to their normal position in the bottom of the scrotum, staying in high or low abdomen, inguine canal, ectopic, suprascrotal or high scrotal position. Although there is no uniform definition for the disorder and, therefore, the statistical results may vary, 2-4% is generally accepted figure for the full-term male births. In 50% of the cases, the testes spontaneously descend during the first months of the infants' life, so the frequency of true cryptorchidism is recorded at a rate of 1-2%. More incidents of the disorder occur in low birth weight males, prematurity, small size for gestational age and twins. The main causes of the cryptorchidism are considered genetic factors (chromosome abnormalities), hormones (especially, INS3-like factor) and environmental contributors (specifically, endocrine disruptors). Whereas the action of hormones and endocrine disruptors may have mild effect, the possible synergy of the three mentioned causes may act unpredictably. The cryptorchidism treatment includes hormonal therapy and surgery, whereas unsuccessful cases of hormonal treatment should immediately be operated before the child's first birthday. The undescended testicles have negative consequences for adults increasing the risk of testicular cancer and infertility, where patients with bilateral form of disorder tend to suffer more than unilateral. Although the treatment and surgery methods are used to solve the problem, around one third of cryptorchidism males appear to be infertile in adulthood. Generally, the clear mechanism of how the cryptorchidism contributes to testicular cancer has not been found yet, nonetheless the studies revealed that cases with early age surgery of the disorder have less percent age of testicular cancer. Therefore, it is essential that the male children with true cryptorchidism be operated at a younger age.