Cryptorchidism

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saumya Easaw, M.B.B.S.[2]

Cryptorchidism is the absence of one or both testes from the scrotum. This usually represents failure of the testis to move, or descend, during fetal development from an abdominal position, through the inguinal canal, into the ipsilateral scrotum. About 3% of full-term and 30% of premature infant boys are born with at least one undescended testis, making cryptorchidism the most common birth defect of male genitalia. However, most testes descend by the first year of life (the majority within three months), making the true incidence of cryptorchidism around 1% overall.

Cryptorchidism is derived from the Greek words “crypto” (meaning “hidden”) and “orchid” (meaning “testicle”). During the last century, cryptorchidism was sometimes restricted to the subset of undescended testes that were not palpable above the scrotum or in the inguinal canal — those that were truly hidden in the abdomen or completely absent. In recent decades the distinction is no longer made in most contexts, and the two terms are used interchangeably. Cryptorchism is an older variant of the same term.

There are usually no symptoms, except that the testicle cannot be found in the scrotum (this may be described as an empty scrotum).

The most common diagnostic dilemma in otherwise normal boys is distinguishing a retractile testis from a testis that will not/cannot descend spontaneously into the scrotum. Retractile testes are more common than truly undescended testes and do not need to be operated on. In normal males, as the cremaster muscle relaxes or contracts, the testis moves lower or higher (“retracts”) in the scrotum. This cremasteric reflex is much more active in infant boys than older men. A retractile testis high in the scrotum can be difficult to distinguish from a position in the lower inguinal canal. Though there are various maneuvers used to do so, such as using a crosslegged position, soaping the examiner’s fingers, or examining in a warm bath, the benefit of surgery in these cases can be a matter of clinical judgement.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saumya Easaw, M.B.B.S.[2]

Cryptorchidism is derived from the Greek words “crypto” (meaning “hidden”) and “orchid” (meaning “testicle”). During the last century, cryptorchidism was sometimes restricted to the subset of undescended testes that were not palpable above the scrotum or in the inguinal canal — those that were truly hidden in the abdomen or completely absent. In recent decades the distinction is no longer made in most contexts, and the two terms are used interchangeably. Cryptorchism is an older variant of the same term.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saumya Easaw, M.B.B.S.[2]

The testes begin as an immigration of primordial germ cells into testicular cords along the genital ridge in the abdomen of the early embryo. The interaction of several male genes organizes this developing gonad into a testis rather than an ovary by the second month of gestation. During the 3rd to 5th months, the cells in the testes differentiate into testosterone-producing Leydig cells, and anti-müllerian hormone-producing Sertoli cells. The germ cells in this environment become fetal spermatogonia. Male external genitalia during the 3rd and 4th months of gestation and the fetus continues to grow, develop, and differentiate.

The testes remain high in the abdomen until the 7th month of gestation, when they move from the abdomen through the inguinal canals into the two sides of the scrotum. It has been proposed that movement occurs in two phases, under control of somewhat different factors. The first phase, movement across the abdomen to the entrance of the inguinal canal appears controlled (or at least greatly influenced) by anti-müllerian hormone (AMH). The second phase, in which the testes move through the inguinal canal into the scrotum, is dependent on androgens (most importantly testosterone). In rodents, androgens induce the genitofemoral nerve to release calcitonin gene-related peptide (CGRP), which produces rhythmic contractions of the gubernaculum, a ligament which connects the testis to the scrotum, but a similar mechanism has not been demonstrated in humans. Maldevelopment of the gubernaculum, or deficiency or insensitivity to either AMH or androgen therefore can prevent the testes from descending into the scrotum. Some evidence suggests there may even be an additional paracrine hormone, referred to as descendin, secreted by the testes.

In many infants with inguinal testes, further descent of the testes into the scrotum occurs in the first 6 months of life. This is attributed to the postnatal surge of gonadotropins and testosterone that normally occurs between the first and fourth months of life.

Spermatogenesis continues after birth. In the 3rd to 5th months of life, some of the fetal spermatogonia residing along the basement membrane become type A spermatogonia. More gradually, other fetal spermatogonia become type B spermatogonia and primary spermatocytes by the 5th year after birth. Spermatogenesis arrests at this stage until puberty.

Most normal-appearing undescended testis are also normal by microscopic examination, but reduced spermatogonia can be found. The tissue in undescended testes becomes more markedly abnormal (“degenerates”) in microscopic appearance between 2 and 4 years after birth. There is some evidence that early orchiopexy reduces this degeneration.

A testis absent from the normal scrotal position can be:

• Found anywhere along the “path of descent” from high in the posterior (retroperitoneal) abdomen, just below the kidney, to the inguinal ring
• Found in the inguinal canal
• Ectopic, that is, found to have “wandered” from that path, usually outside the inguinal canal and sometimes even under the skin of the thigh, the perineum, the opposite scrotum, and femoral canal
• Found to be undeveloped (hypoplastic) or severely abnormal (dysgenetic)
• Found to have vanished (also see Anorchia)

About two thirds of cases without other abnormalities are unilateral; 1/3 involve both testes. In 90% of cases an undescended testis can be palpate (felt) in the inguinal canal; in a minority the testis or testes are in the abdomen or nonexistent (truly “hidden”).

Undescended testes are associated with reduced fertility, increased risk of testicular germ cell tumors and psychological problems when the boy is grown. Undescended testes are also more susceptible to testicular torsion and infarction and inguinal hernias. To reduce these risks, undescended testes are usually brought into the scrotum in infancy by a surgical procedure called an orchiopexy.

Although cryptorchidism nearly always refers to congenital absence or maldescent, a testis observed in the scrotum in early infancy can occasionally “reascend” (move back up) into the inguinal canal. A testis which can readily move or be moved between the scrotum and canal is referred to as retractile.

Cryptorchidism occurs at a much higher rate in a large number of congenital malformation syndromes. Among the more common are:

• Cloacal exstrophy
• Noonan syndrome
• Prader-Willi syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saumya Easaw, M.B.B.S.[2]

In most full-term infant boys with cryptorchidism but no other genital abnormalities, a cause cannot be found, making this a common, sporadic, unexplained (idiopathic) birth defect.

Although severely premature infants can be born before descent of testes, there is a strong association of cryptorchidism with low birth weight due to either prematurity or intrauterine growth retardation. In these infants there is usually no evidence of hormonal malfunction. Associated inguinal hernias are common.

Hormonal abnormalities (deficiency or insensitivity to androgens or anti-müllerian hormone) can be demonstrated in a high proportion of those with evidence of undervirilization or ambiguity such as hypospadias or micropenis.

A contributing role of environmental chemicals — endocrine disruptors — that interfere with normal fetal hormone balance has been proposed as well, similar to the effects of diethylstilbestrol exposure. It is rarely possible to implicate a specific chemical exposure for an individual child.

Occasional instances of other genetic defects involving development or function of the gubernaculum have been reported. Homeobox gene mutations can cause cryptorchidism in animals but remain a largely theoretical possibility in humans.

Rare iatrogenic cases have also been reported in which hernia repair or other surgery in the inguinal area resulted in trapping of a testis above the scrotum.

A 2006 study showed that regular alcohol consumption during pregnancy (5 or more drinks per week) is associated with a 3x increase in cryptorchidism, when compared to non-drinking mothers. Other previously known risk factors include exposure to pesticides, low birth weight (including premature birth), gestational diabetes and being a twin.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saumya Easaw, M.B.B.S.[2]

Many men who were born with undescended testes have reduced fertility, even after orchiopexy in infancy. The reduction with unilateral cryptorchidism is subtle, with a reported infertility rate of about 10%, compared with about 6% reported by the same study for the general population of adult men.

The fertility reduction after orchiopexy for bilateral cryptorchidism is more marked, about 38%, or 6 times that of the general population. The basis for the universal recommendation for early surgery is research showing degeneration of spermatogenic tissue and reduced spermatogonia counts after the second year of life in undescended testes. The degree to which this is prevented or improved by early orchiopexy is still uncertain.

At least one contributing mechanism for reduced spermatogenesis in cryptorchid testes is temperature. The temperature of testes in the scrotum is at least a couple of degrees cooler than in the abdomen. Animal experiments in the middle of the 20th century suggested that raising the temperature could damage fertility. Some circumstantial evidence suggests tight underwear and other practices that raise testicular temperature for prolonged periods can be associated with lower sperm counts. Nevertheless, research in recent decades suggests that the issue of fertility is more complex than a simple matter of temperature. It seems likely that subtle or transient hormone deficiencies or other factors that lead to lack of descent also impair the development of spermatogenic tissue.

The inhibition of spermatogenesis by ordinary intra-abdominal temperature is so potent that continual suspension of normal testes tightly against the inguinal ring at the top of the scrotum by means of special “suspensory briefs” has been researched as a method of male contraception, and was referred to as “artificial cryptorchidism” by one report.

An additional factor contributing to infertility is the high rate of anomalies of the epididymis in boys with cryptorchidism (over 90% in some studies). Even after orchiopexy, these may also affect sperm maturation and motility at an older age.

One of the strongest arguments for early orchiopexy is prevention of testicular cancer. About 1 in 500 men born with one or both testes undescended develops testicular cancer, roughly a 4- to 40-fold increased risk. The peak incidence occurs in the 3rd and 4th decades of life. The risk is higher for intra-abdominal testes and somewhat lower for inguinal testes, but even the normally descended testis of a man whose other testis was undescended has about a 20% higher cancer risk than those of other men.

The most common type of testicular cancer occurring in undescended testes is seminoma. It is usually treatable if caught early, so urologists often recommend that boys who had orchiopexy as infants be taught testicular self-examination, to recognize testicular masses and seek early medical care for them. Cancer developing in an intra-abdominal testis would be unlikely to be recognized before considerable growth and spread, and one of the advantages of orchiopexy is that a mass developing in a scrotal testis is simply far easier to recognize than an intra-abdominal mass.

Although orchiopexy makes cancer more easily recognizable at an early stage, whether early orchiopexy actually reduces the chance of developing cancer remains a subject of controversy. As with infertility, the causes of cancer associated with cryptorchidism are not known. Most evidence suggests the cancer risk is due to an inherent abnormality of the undescended testis rather than to the ability of an abdominal location to cause cancer in an otherwise normal testis.

The risk of malignancy in the undescended testis is 4 to 10 times higher than that in the general population and is approximately 1 in 80 with a unilateral undescended testis and 1 in 40 to 1 in 50 for bilateral undescended testes. The peak age for this tumor is 15–45 yr. The most common tumor developing in an undescended testis is a seminoma (65%); in contrast, after orchiopexy, seminomas represent only 30% of testis tumors.

A small percentage of cases of isolated cryptorchidism are familial. It has been reported that about 4% of fathers and 6-10% of brothers of affected boys have also had cryptorchidism. Few specific genes associated with isolated cryptorchidism have been identified.

In contrast, many of the genes causing some of the intersex conditions associated with androgen or AMH deficiency or insensitivity have been identified, and genetic counseling to explain recurrence risk to families is appropriate.

A new study shows that pregnant women who drink caffeine (at least 3drinks per day*) will increase the risk of cryptorchidism.

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