Cryptorchidism

Etiology

A normal hypothalamic-pituitary-gonadal axis is a prerequisite for normal testicular descent, as it coordinates hormonal signals necessary for the developmental process. The absence of an appendix testis has been associated with abdominal and cryptorchid testes, mainly when located proximal to the external ring. However, the exact role of the appendix testis in testicular descent remains unclear.

The cause of cryptorchidism is often indeterminate in full-term infants, rendering it a common yet sporadic, idiopathic congenital abnormality. Experts believe that a combination of genetics, maternal factors, and environmental influences may disrupt the hormonal and physical processes that influence testicular development and descent. 

Birth weight is the primary risk factor for undescended testes, followed by family history. Furthermore, other potential contributing risk factors include:

• Alcohol consumption during pregnancy (5 or more drinks per week, which can increase the risk up to 3 times)
• Chemical endocrine disruptors interfering with normal fetal hormone balance
• Cigarette smoking
• Congenital malformation syndromes such as Down syndrome, Prader–Willi syndrome, and Noonan syndrome
• Cosmetics use
• Exposure to phthalate (di[2-ethylhexyl] phthalate or DEHP)
• Family history of cryptorchidism
• Ibuprofen use
• In vitro fertilization
• Maternal diabetes
• Maternal exposure to diethylstilbestrol 
• Maternal obesity
• Persistent Müllerian duct syndrome
• Pesticide exposure
• Preeclampsia (especially in its more severe forms, poses an increased risk of cryptorchidism)
• Premature infants born before the descent of the testicles
• Small for gestational-age infants
• Smaller placental weight [1][2]

Epidemiology

Cryptorchidism is observed in 3% of full-term newborn infants, with this prevalence decreasing to 1% in infants aged 6 months to 1 year.[1][2] In the US, cryptorchidism ranges from approximately 3% at birth to 1% from 1 year to adulthood. Globally, the prevalence varies, starting at around 4% to 5% at birth, decreasing to about 1% to 1.5% at age 3 months, and further decreasing to 1% to 2.5% at 9 months. The prevalence of cryptorchidism is 30% in premature male neonates. This elevated prevalence highlights the significance of closely monitoring testicular development and considering timely interventions when necessary.

Cryptorchidism affects approximately 1.5% to 4% of fathers and 6% of brothers of individuals with cryptorchidism. The heritability in first-degree male relatives is estimated to be around 0.5% to 1%. Additionally, 7% of siblings of boys with undescended testes also experience cryptorchidism, emphasizing its potential genetic predisposition within families. Ongoing research aims to understand the nature and significance of the possible association between cryptorchidism and autism.

Pathophysiology

Unlike the scrotum, the altered microenvironment within the abdominal cavity or inguinal canal can disturb the optimal conditions for normal testicular function. The scrotum provides a cooler temperature, essential for the proper functioning of the testes and the production of sperm. Elevated temperature in the abdominal or inguinal region can adversely impact sperm development and fertility.

Cryptorchidism can disrupt communication between the testes and the endocrine system, potentially leading to transient hormone deficiencies. These hormonal imbalances may contribute to the failure of testicular descent and impede the development of the spermatogenic tissue, consequently compromising fertility.[3]

History and Physical

The most apparent sign in a patient with a cryptorchid testis is the absence of a palpable scrotal testicle. An inguinal hernia and decreased scrotal rugae or ridges are often present. A thorough examination of the entire inguinal and pelvic area, including an evaluation of the contralateral testicle, is essential. If a scrotum exhibits normal rugae and contains a testicle, it may suggest a retractile testicle, typically not necessitating further treatment. Although changes in the scrotum are frequently observed in cryptorchidism, patients may also present with additional signs and symptoms. Some common associations with undescended testicles include the following.

Infertility

Several factors contribute to reduced fertility in those with cryptorchidism. One key factor is hyperthermia, which can impair spermatogenesis, as the intrascrotal temperature is several degrees cooler than ectopic positions. Various anatomical abnormalities, such as testis-epididymal dissociation, are commonly associated with undescended testes. In some cases, accidental injury to the vas deferens, epididymis, or testis may occur during orchiopexy procedures. A higher incidence of anti-sperm antibodies exists in infertile patients with a history of cryptorchidism.[5][6]

Factors influencing abnormal testicular descent, whether due to chemical exposure or other etiological factors, are likely to have affected both testicles, not just the cryptorchid testis. However, identifying a specific causative defect or disorder may not be determinable. Men with undescended testes often face reduced fertility, which may persist even following orchiopexy.[7] Specifically, approximately 10% to 30% of patients with a unilateral cryptorchid testicle will develop infertility, and azoospermia is found in 13% of individuals with unilateral undescended testicles.[5] In contrast, azoospermia rates can increase to around 90% in patients with untreated bilateral cryptorchidism.[5] 

Even after orchiopexy for bilateral cryptorchidism, fertility remains significantly diminished, estimated at least 38%. This fact emphasizes the universal recommendation for early surgical intervention, as untreated undescended testes can undergo degeneration of spermatogenic tissue and reduced spermatogonia after the second year of life, further compromising fertility prospects.

Psychological Consequences

Boys with undescended testicles are not inherently more predisposed to exhibit gender-related disorders, effeminate traits, or prehomosexual characteristics. However, in cases where family dynamics are detrimental to self-esteem, it can lead to disturbances in self-image. The surgical correction of cryptorchidism typically fosters the development of a healthy sense of masculinity. 

Cancer

The risk of testicular cancer is approximately 3 times higher than that of the general population when orchiopexy is performed before puberty. However, this risk increases to 5 to 6 times higher when orchiopexy is conducted after puberty. The timing of orchiopexy, whether in early infancy or later in childhood, does not appear to significantly affect the risk of developing testicular cancer.[7]

Seminoma is the most prevalent type of testicular cancer found in untreated undescended testes, with the peak age range for this tumor occurring between the ages of 15 and 45. However, following orchiopexy, seminomas account for only 30% of testicular tumors in previously undescended testes. Early detection is crucial for the effective treatment of testicular cancer. Educating boys who underwent orchiopexy as infants about testicular self-examination is essential to facilitate timely cancer detection.

Evaluation

According to American Urological Association (AUA) guidelines: "In the hands of an experienced provider, more than 70% of cryptorchid testes are palpable by physical examination and need no imaging. In the remaining 30% of cases with nonpalpable testis, the challenge is to confirm the testis's absence or presence and identify the location of the viable nonpalpable testis."[8] 

Routine ultrasound usage is generally unhelpful, as it exhibits limited sensitivity and specificity in localizing nonpalpable testes, with reported values of 45% sensitivity and 78% specificity.[9] Furthermore, data indicate that among boys with a nonpalpable testicle and a negative ultrasound, 49% are ultimately found to have an intra-abdominal testis.[9]

The utilization of computed tomography is limited due to cost and concerns about ionizing radiation exposure. Magnetic resonance imaging, often used with or without angiography, demonstrates greater sensitivity and specificity. However, its use is discouraged due to the associated high cost, limited availability, and the requirement for anesthesia.[10] Currently, no radiological test can definitively and with absolute reliability confirm the absence of a testis. Multiple studies have indicated that, regardless of the findings of radiological tests, they rarely provide conclusive assistance in decision-making. They may sometimes offer misleading information, such as indicating absence when the testis is present or vice versa.[11]

A karyotype analysis can confirm or rule out dysgenetic primary hypogonadism. Hormone levels, such as gonadotropins and Müllerian inhibitory substance, may confirm hormonally functional testicles suitable for preservation. Additionally, human chorionic gonadotropin (hCG) stimulation can elevate testosterone levels. In certain instances, further testing is imperative and highly probable to detect intersex conditions.[7]

Bilateral Cryptorchidism

Bilateral cryptorchidism with palpable testes can be addressed through surgery, although there is some debate regarding the optimal timing for this intervention. Some experts advocate for 2 separate procedures, allowing complete healing of 1 testicle before addressing the contralateral side. Although this approach ensures the survival of at least 1 testicle, it requires subjecting a young child to 2 separate procedures and anesthesia. Consequently, many specialists prefer to repair both sides in a single surgery, primarily due to the overall low complication rate of about 1%.[12] Infertility may be observed in 35% to 75% of men who initially presented with bilateral cryptorchidism during childhood.

Patients with bilateral impalpable testes, a condition that can affect approximately 20% to 30% of all boys with cryptorchidism, require further evaluation to investigate the potential presence of a disorder of sexual development.[13] Any circumcision procedures should be withheld until the evaluation is complete.

In some instances, individuals born with female genetics and severe congenital adrenal hyperplasia may be initially misidentified as males with bilateral cryptorchidism. The initial action should involve assessing the patient for possible congenital adrenal hyperplasia. This includes measuring electrolytes for hyponatremia and hyperkalemia, conducting karyotype analysis, and performing hormonal profiling, including androstenedione, 17-hydroxyprogesterone, luteinizing hormone, follicle-stimulating hormone (FSH), and testosterone hormones.[8]

After ruling out congenital adrenal hyperplasia, the next step is to ascertain the presence of testicular tissue. The presence of anti-Müllerian hormone, produced by the testicular Sertoli cells, would indicate the presence of testicular tissue somewhere, possibly intra-abdominal. FSH can stimulate the production of inhibin B and anti-Müllerian hormone, whereas hCG can stimulate Leydig cells to produce testosterone.[14] 

Patients possessing a male karyotype (46, XY chromosomes), bilateral nonpalpable testes, elevated serum FSH levels, and no detectable serum anti-Müllerian hormone and inhibin B can be reasonably diagnosed as having no testicular tissue (anorchia).[14] Although hCG stimulation testing has been conducted in the past, an undetectable anti-Müllerian hormone offers a notably superior positive predictive value at 92%.[15] In instances where testicular tissue is presumed to be present, an exploratory laparoscopy can be performed to determine the location of the testicular tissue and the optimal surgical approach.

Treatment / Management

Medical Treatment

According to the AUA guidelines, healthcare professionals are advised against hormonal therapy to induce testicular descent, citing low response rates and a lack of long-term efficacy.[8] This recommendation is in line with the guidelines of several respected medical organizations, including the European Society for Pediatric Urology, the European Association of Urology (EAU), the Canadian Urological Association, the British Association of Pediatric Surgeons, and the British Association of Pediatric Urology Surgeons.[7][16][17][18](A1)

The American Pediatric Association guidelines recommend the use of hormones in patients with undescended testis associated with Prader-Willi syndrome. The rationale stems from the belief that a therapeutic trial of hCG is indicated as a treatment for undescended testes before surgical intervention. This approach is motivated by the preference to avoid general anesthesia in infants with low muscle tone and at high risk for underlying respiratory compromise.

The primary hormone utilized for hormone therapy is hCG. A course of hCG injections is administered, and then the status of the undescended testicle is reassessed. The reported success rate for this treatment method ranges from 5% to 50%. In addition, hormone treatment serves the dual purpose of confirming Leydig cell responsiveness and stimulating further growth of a small penis due to the elevation in testosterone levels. 

Hormone therapy is often considered a more cost-effective alternative to surgery, with a minimal risk of complications. However, a recent meta-analysis of results from 7 randomized clinical trials found that hormonal treatment exhibited no greater efficacy than a placebo.[16](A1)

Surgery

According to the AUA guidelines, surgery is advised for congenital undescended testes between the ages of 6 and 18 months.[8] Many specialists endorse early surgical intervention, often around 6 months, to optimize testicular growth and preserve fertility. Furthermore, performing the procedure at a younger age is preferable because the distance the testes must be moved increases as the child ages.

Unfortunately, many young boys do not undergo orchidopexy within the recommended guidelines. A study reported that 70% of those with undescended testes underwent surgery at least 6 months later than advised.[19] The reasons for this delay were varied, including secondary cryptorchidism, decreased well-child visits, familial challenges, and a tendency to rely on family caregivers for surgical referrals rather than pediatricians. This suggests the possibility of inadequate examinations or insufficient familiarity with the guidelines among some practitioners.[20][21] Additionally, race and insurance status were identified as significant contributing factors.[21][22] For every 6-month delay in performing the orchidopexy, patients may experience a 1% decrease in fertility, a 5% increase in the necessity for assisted reproductive techniques, and a 6% increased risk of developing testicular malignancy later in life.[20] (B2)

In the case of premature babies, corrected age is used to determine optimal surgical timing. The longer the cryptorchid testis remains untreated, the more significant the loss of germ cell becomes as well as the subsequent decrease in fertility. Therefore, early orchidopexy is typically the standard intervention.[4] Patients with bilateral undescended testes who undergo orchidopexies as adults are almost invariably infertile and exhibit azoospermia. However, there have been a few anecdotal reports of pregnancies achieved through assisted reproduction in this group.[23]

Surgery is recommended promptly following diagnosis for acquired undescended testes (those identified as normal before diagnosis) and entrapped undescended testes (those occurring after hernia repair). Conversely, an annual physical examination is recommended for retractile testes due to the reported risk of 2% to 50% of a retractile testis potentially transitioning into an acquired undescended testis. 

Techniques of Orchiopexy

For palpable undescended testes, performing an inguinal or scrotal orchiopexy is recommended.[23] The procedure typically involves the following factors:

• Depending on the case, an incision is made in the high scrotum, median scrotal raphe, high edge of the scrotum, or groin. Many different types of retractors can be used depending on the incision size. Inguinal incisions can be as small as 1 cm, whereas scrotal incisions can be larger as they tend to heal concealed, especially when placed along the median raphe. 
• The surgeon can choose to approach either the testis or the cord first. In scrotal cases, the testis is typically located first. In an inguinal approach, the testis can be approached first, or the external oblique fascia is opened proximal to the external ring, and the cord can be accessed first. 
• The surgeon initially divides all the cremasteric muscles before approaching the testis, as not everything goes into the external ring.
• A more challenging aspect of the procedure is separating the hernia sac from the vas deferens and testicular vessels. This can be approached anteriorly or posteriorly, with the posterior approach typically easier to teach and learn.
• How the testis is positioned and secured in the scrotum can vary among surgeons. Most surgeons prefer to create a sub-dartos pouch. Some surgeons do not suture the testis in place, while others use absorbable or nonabsorbable sutures. Alternatively, some may choose to close the passage into the groin. 

For nonpalpable testes under anesthesia, exploratory laparoscopy is the recommended approach. During exploratory laparoscopy, if a testis is discovered, the surgeons perform any of the following available options for their patients.

Laparoscopic orchiopexy with preservation of the vessels: This procedure involves dissecting the testis from a triangular pedicle containing the gonadal vessels and the vas deferens.

Laparoscopic 1-stage Fowler-Stephens orchiopexy: In this process, the gonadal vessels are divided, and the testis is dissected off a pedicle of the vas deferens, bringing it down in one stage.

Laparoscopic 2-stage Fowler-Stephens orchiopexy: This technique uses clips to divide the gonadal vessels. However, dissection of the testis is deferred for 6 months, allowing for optimal development of collaterals before proceeding with the testicular relocation.

Laparoscopic 2-stage traction-orchidopexy (Shehata technique): In this procedure, the intra-abdominal testis is fixed to a point 1 inch (2 cm) medially and superiorly to the contralateral anterior superior iliac spine to provide traction. The testis remains in its undescended position for 3 months. Afterward, a laparoscopy-assisted ipsilateral subdartos orchidopexy is performed. This technique is an alternative to the 2-stage Fowler-Stephens (FS) orchidopexy.[23][24][25][26][27] (B2)

The primary advantage of the Shehata technique is that it can relocate an intra-abdominal testis into the scrotum without sacrificing the main testicular vessels. This technique requires only a 3-month delay, whereas the FS method needs 6 months. The Shehata technique should be considered in cases where a single-stage laparoscopic orchidopexy cannot be performed due to inadequate length. This procedure has a very high success rate of preserving testicular vasculature and minimizing the risk of atrophy. Study results have reported an overall success rate ranging from 84% to 100% with this approach.[24][25](B2)

A testicular ischemia test has been suggested to assess the feasibility of an FS orchidopexy. During laparoscopic surgery, the spermatic cord vessels are temporarily tied off with a silk ligature that can easily be loosened. After a 10-minute interval, the testis is re-examined and compared to its appearance before the cord ligation. If no signs of ischemic changes are observed in the testis, it indicates an adequate collateral blood supply, suggesting the safety of proceeding with an FS surgical approach.[28](B2)

Systematic comparison and meta-analysis of the 2 laparoscopic 2-staged surgical procedures concluded that the Shehata internal fixation technique exhibited superior overall success and a lower atrophy rate when compared to the FS approach. No significant difference was noted in the retraction rate or operative time.[29] (A1)

The selection of a surgical approach depends on the surgeon's specific training, experience, skill level, and personal preference. The Shehata technique is theoretically preferred as it does not sacrifice the testicular artery and has a lower rate of gonadal atrophy. This method is particularly recommended for patients who fail the testicular ischemia test.

If no testis is located during exploratory laparoscopy, it becomes crucial to ascertain the presence of either blind-ending vessels or a testicular nubbin to rule out a missing testis definitively. The vas deferens can be dissociated from the testis, making it unreliable as a sole guide in locating the gonad.[23]

If the internal ring is closed but vessels are observed entering it, a scrotal exploration typically reveals a testicular nubbin. This nubbin will appear as a small structure with a brown spot. Upon entering an open inguinal ring, pushing the testis into the abdomen is usually possible. However, an inguinal or scrotal exploration is warranted if this cannot be accomplished.

Differential Diagnosis

A typical diagnostic challenge involves differentiating a retractile testicle from a testicle that does not spontaneously descend into the scrotum. Retractile testes are more prevalent than undescended testes and do not necessitate surgical correction. The cremaster muscle contracts in normal instances, causing the testicles to retract into the upper scrotum and inguinal canal. This reflex is more active in infants. 

Distinguishing a retractile testicle positioned high in the scrotum from one in the lower inguinal canal can be challenging. Various maneuvers are used to aid in identification, such as having the patient in a cross-legged position, using soaped fingers during examination, and assessing the patient while in a warm bath.

According to the AUA guidelines, a retractile testis is described as initially located outside the scrotum or easily movable out of it, typically associated with the cremasteric reflex. However, at least temporarily, it can be manually returned to a stable, dependent scrotal position without tension.[8]

Prognosis

With proper diagnosis and treatment, the prognosis for cryptorchidism is excellent. However, there is a slight increase in the risks of testicular cancer and infertility compared to the general population.[30] A Danish study involving over 6000 men indicated that individuals with a history of cryptorchidism exhibited testicular hypofunction, with a 3.5 mL reduction in testis volume, a 28% reduction in sperm concentration, and diminished Leydig cell function compared to men without cryptorchidism.[31]

Complications

Orchiopexy is associated with 2 major testicular complications—atrophy and testicular ascent.[2] These complications occur in approximately 1% of the time for palpable testes. The rate increases to around 5% for laparoscopic orchiopexies. In FS orchiopexies, whether performed in 1 or 2 stages, the rate of testicular atrophy is around 20% to 30%, with the 1-stage procedure resulting in worse outcomes.[32] Over-skeletonization of the spermatic cord leading to the loss of the testis represents a severe complication of orchiopexy.