BIOCHEMISTRY OF CRYTORCHIDISM

BY

NWACHUKWU, FAITH SOROCHI

2019/ND/SLT/85625

A SEMINAR PRESENTED TO THE DEPARTMENT OF SCIENCE

LABORATORY TECHNOLOGY, IMO STATE POLYTECHNIC
UMUAGWO
IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE
AWARD OF NATIONAL DIPLOMA IN SCIENCE LABORATORY
TECHNOLOGY

SUPERVISED BY: DR. OSUOHA, J.O

DECEMBER, 2021

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 OVERVIEW

The condition known as cryptorchidism – undescended testis – is one of the most

common congenital abnormalities found among males, and is one of the few known risk
factors for testicular cancer (TC). Like testicular cancer, the key exposures in the
occurrence of cryptorchidism remain elusive. Testicular descent is thought to occur
during two hormonally-controlled phases – between 8–15 weeks and 25–35 weeks
gestation – and while it is clear that a failure of testes to descend permanently is likely
due to disruptions to one or both of these phases, the cause(s) and mechanism(s) of
such disruption are still unclear. In this manuscript, we review the broad range of
putative risk factors that have been evaluated in relation to the development of
cryptorchidism to date, discuss their plausibility, and make suggestions regarding
further approaches to understand aetiology. There are few exposures for which there is
consistent evidence of an association with cryptorchidism; and in those cases where
evidence appears unequivocal – for example, the relationship between cryptorchidism
and gestational measures such as low birth weight – the measured exposure is likely to
be a surrogate for the true causal exposure. The relative importance of each risk factor
may vary considerably between mother/son pairs depending on an array of genetic,
maternal, placental and foetal factors – all of which could vary between regions

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 TABLE OF CONTENTS

Title page i

Overview ii

Table of contents iii

Introduction 1

History of cryptorchidism 3

Signs and symptoms of cryptorchidism 4

Causes of cryptorchidism 6

Mechanism of cryptorchidism 8

Diagnosis of cryptorchidism 11

Treatment of cryptorchidism 12

Conclusion 15

References 16

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 INTRODUCTION

Cryptorchidism is the absence of one or both testes from the scrotum. The
word is from the Greek κρυπτός (kryptos), meaning "hidden", and ὄρχις
(orchis), meaning "testicle". It is the most common birth defect of the male
genital tract. About 3% of full-term and 30% of premature infant boys are
born with at least one undescended testis. However, about 80% of
cryptorchid testes descend by the first year of life (the majority within
three months), making the true incidence of cryptorchidism around 1%
overall. Cryptorchidism may develop after infancy, sometimes as late as
young adulthood, but that is exceptional. (Amann, 2007)

Cryptorchidism is distinct from monorchism, the condition of having only

one testicle. Though the condition may occur on one or both sides, it more
commonly affects the right testis.

A testis absent from the normal scrotal position may be:

1. Anywhere along the "path of descent" from high in the posterior

(retroperitoneal) abdomen, just below the kidney, to the inguinal ring
2. In the inguinal canal
3. Ectopic, having "wandered" from the path of descent, usually outside
the inguinal canal and sometimes even under the skin of the thigh,
the perineum, the opposite scrotum, or the femoral canal
4. Undeveloped (hypoplastic) or severely abnormal (dysgenetic)
5. Missing (also see anorchia).

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Fig. 1: Diagram of Cryptorchidism

About two-thirds of cases without other abnormalities are unilateral; most

of the other third involve both testes. In 90% of cases, an undescended
testis can be felt in the inguinal canal. In a small minority of cases, missing
testes may be found in the abdomen or appear to be nonexistent (truly
"hidden"). (Brouwers, 2012)

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 subsequent infarction) and inguinal hernias. Without intervention, an
undescended testicle will usually descend during the first year of life, but to
reduce these risks, undescended testes can be brought into the scrotum in
infancy by a surgical procedure called an orchiopexy.

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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
that can readily move or be moved between the scrotum and canal is
referred to as retractile.

Cryptorchidism, hypospadias, testicular cancer, and poor semen quality

make up the syndrome known as testicular dysgenesis syndrome. (Griffin,
2005)

HISTORY OF CRYPTORCHIDISM

Cryptorchidism has been recognized for centuries. It was first described in

the medical literature in 1786 by Hunter. The first surgical orchiopexy was
attempted in 1820 by Rosenmerkal. However, it was not until 1877 that
Annandale performed the first successful orchiopexy (Leslie, 2021)
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SIGNS AND SYMPTOMS OF CRYPTORCHIDISM

 Infertility

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. (Memon, 2001)

The fertility reduction after orchiopexy for bilateral cryptorchidism is more

marked, about 38%, or six 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.

 Cancer risk

One of the strongest arguments for early orchiopexy is reducing the risk of
testicular cancer. About one in 500 men born with one or both testes
undescended develops testicular cancer, roughly a four- to 40-fold
increased risk. The peak incidence occurs in the third and fourth 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
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other testis was undescended has about a 20% higher cancer risk than
those of other men. (Meyers-Wallen, 2006)

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 far easier to recognize than an intra-abdominal mass.
(Pelley, 2008)

Orchidopexy was originally thought to result in easier detection of testicular

cancer, but did not lower the risk of actually developing cancer. However,
recent data have shown a paradigm shift. The New England Journal of
Medicine published in 2007 that orchidopexy performed before puberty
resulted in a significantly reduced risk of testicular cancer than if done after
puberty.

The risk of malignancy in the undescended testis is four to 10 times higher

than that in the general population and is about one in 80 with a unilateral
undescended testis and one in 40 to one in 50 for bilateral undescended
testes. The peak age for this tumor is 15–45 years old. The most common
tumor developing in an undescended testis is a seminoma (65%); in
contrast, after orchiopexy, seminomas represent only 30% of testicular
tumors. (Scott, 2002)

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CAUSES OF CRYPTORCHIDISM

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. A combination of genetics, maternal
health, and other environmental factors may disrupt the hormones and
physical changes that influence the development of the testicles.
(Tamparo, 2011)

 Severely premature infants can be born before descent of testes. Low

birth weight is also a known factor.
 A contributing role of environmental chemicals called endocrine
disruptors that interfere with normal fetal hormone balance has been
proposed. The Mayo Clinic lists "parents' exposure to some
pesticides" as a known risk factor.
 Risk factors may include exposure to regular alcohol consumption
during pregnancy (five or more drinks per week, associated with a
three-fold increase in cryptorchidism when compared to nondrinking
mothers. Cigarette smoking is also a known risk factor.
 Family history of undescended testicles or other problems of genital
development

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  Cryptorchidism occurs at a much higher rate in a large number of
congenital malformation syndromes. Among the more common are
Down syndrome, Prader–Willi syndrome, and Noonan syndrome.
 In vitro fertilization, use of cosmetics by the mother, and pre-
eclampsia have also been recognized as risk factors for development
of cryptorchidism.

In 2008, a study was published that investigated the possible relationship

between cryptorchidism and prenatal exposure to a chemical called
phthalate (DEHP), which is used in the manufacture of plastics. The
researchers found a significant association between higher levels of DEHP
metabolites in pregnant mothers and several sex-related changes,
including incomplete descent of the testes in their sons. According to the
lead author of the study, a national survey found that 25% of U.S. women
had phthalate levels similar to the levels that were found to be associated
with sexual abnormalities. (Amann, 2007)

A 2010 study examined the prevalence of congenital cryptorchidism among

offspring whose mothers had taken mild analgesics, primarily over-the-
counter pain medications including ibuprofen (e.g. Advil) and paracetamol
(acetaminophen). Combining the results from a survey of pregnant women
prior to their due date in correlation with the health of their children and an
ex vivo rat model, the study found that pregnant women who had been
exposed to mild analgesics had a higher prevalence of baby boys born with
congenital cryptorchidism. (Andersen, 2008)

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New insight into the testicular descent mechanism has been hypothesized
by the concept of a male programming window derived from animal
studies. According to this concept, testicular descent status is "set" during
the period from eight to 14 weeks of gestation in humans. Undescended
testis is a result of disruption in androgen levels only during this
programming window. (Miller, 2004)

MECHANISM OF CRYPTORCHIDISM

 Normal development

The testes begin as an immigration of primordial germ cells into testicular

cords along the gonadal 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
third to fifth 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 develops during the third and fourth months of gestation
and the fetus continues to grow, develop, and differentiate. The testes
remain high in the abdomen until the seventh month of gestation when
they move from the abdomen through the inguinal canals into the two
sides of the scrotum. Movement has been proposed to occur in two
phases, under the 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

11
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, 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 can, therefore, prevent the testes from
descending into the scrotum. Some evidence suggests an additional
paracrine hormone, referred to as descendin, may be secreted by the
testes. (Memon, 2001)

In many infants with inguinal testes, further descent of the testes into the
scrotum occurs in the first six 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 third to fifth 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 fifth year
after birth. Spermatogenesis arrests at this stage until puberty. (Kristensen,
2011)

Most normal-appearing undescended testes are also normal by microscopic

examination, but reduced spermatogonia can be found. The tissue in
undescended testes becomes more markedly abnormal ("degenerates") in

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microscopic appearance between two and four years after birth. Some
evidence indicates early orchiopexy reduces this degeneration.

 Pathophysiology

At least one contributing mechanism for reduced spermatogenesis in

cryptorchid testes is temperature. The temperature of testes in the scrotum
is at least a few 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 the 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. Subtle or transient
hormone deficiencies or other factors that lead to a lack of descent also
may impair the development of spermatogenic tissue. (Miller, 2004)

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.

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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. (Scott, 2002)

DIAGNOSIS OF CRYPTORCHIDISM

Scrotal ultrasonography of undescended testis:

(a) Normal testis in the scrotum
(b) Atrophic and decreased echogenicity of the contralateral testis of the
same patient seen in the inguinal region

The most common diagnostic dilemma in otherwise normal boys is

distinguishing a retractile testis from a testis that will not 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 various maneuvers are used to do so, such as using a cross-
legged 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
judgment. (Leslie, 2021)
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In the minority of cases with bilaterally nonpalpable testes, further testing
to locate the testes, assess their function, and exclude additional problems
is often useful. Scrotal ultrasound or magnetic resonance imaging
performed and interpreted by a radiologist can often locate the testes while
confirming absence of a uterus. At ultrasound, the undescended testis
usually appears small, less echogenic than the contralateral normal testis
and usually located in the inguinal region. With color Doppler
ultrasonography, the vascularity of the undescended testis is poor.

A karyotype can confirm or exclude forms of dysgenetic primary

hypogonadism, such as Klinefelter syndrome or mixed gonadal dysgenesis.
Hormone levels (especially gonadotropins and AMH) can help confirm that
hormonally functional testes are worth attempting to rescue, as can
stimulation with a few injections of human chorionic gonadotropin to elicit
a rise of the testosterone level. Occasionally, these tests reveal an
unsuspected and more complicated intersex condition. (Andersen, 2008)

In the even smaller minority of cryptorchid infants who have other obvious
birth defects of the genitalia, further testing is crucial and has a high
likelihood of detecting an intersex condition or other anatomic anomalies.
Ambiguity can indicate either impaired androgen synthesis or reduced
sensitivity. The presence of a uterus by pelvic ultrasound suggests either
persistent Müllerian duct syndrome (AMH deficiency or insensitivity) or a
severely virilized genetic female with congenital adrenal hyperplasia. An
unambiguous micropenis, especially accompanied by hypoglycemia or
jaundice, suggests congenital hypopituitarism. (Griffin, 2005)

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TREATMENT OF CRYPTORCHIDISM

The primary management of cryptorchidism is watchful waiting, due to the

high likelihood of self-resolution. Where this fails, orchiopexy is effective if
inguinal testes have not descended after 4–6 months. Surgery is often
performed by a pediatric urologist or pediatric surgeon, but in many
communities still by a general urologist or surgeon. (Memon, 2001)

When the undescended testis is in the inguinal canal, hormonal therapy is

sometimes attempted and very occasionally successful. The most
commonly used hormone therapy is human chorionic gonadotropin (hCG).
A series of hCG injections (10 injections over five weeks is common) is
given and the status of the testis/testes is reassessed at the end. Although
many trials have been published, the reported success rates range widely,
from roughly 5% to 50%, probably reflecting the varying criteria for
distinguishing retractile testes from low inguinal testes. Hormone treatment
does have the occasional incidental benefits of allowing confirmation of
Leydig cell responsiveness (proven by a rise of the testosterone by the end
of the injections) or inducing additional growth of a small penis (via the
testosterone rise). Some surgeons have reported facilitation of surgery,
perhaps by enhancing the size, vascularity, or healing of the tissue. A
newer hormonal intervention used in Europe is the use of GnRH analogs
such as nafarelin or buserelin; the success rates and putative mechanism
of action are similar to hCG, but some surgeons have combined the two
treatments and reported higher descent rates. Limited evidence suggests
that germ cell count is slightly better after hormone treatment; whether

16
this translates into better sperm counts and fertility rates at maturity has
not been established. The cost of either type of hormone treatment is less
than that of surgery and the chance of complications at appropriate doses
is minimal. Nevertheless, despite the potential advantages of a trial of
hormonal therapy, many surgeons do not consider the success rates high
enough to be worth the trouble, since the surgery itself is usually simple
and uncomplicated. (Pelley, 2008)

In cases where the testes are identified preoperatively in the inguinal

canal, orchiopexy is often performed as an outpatient and has a very low
complication rate. An incision is made over the inguinal canal. The testis
with accompanying cord structure and blood supply is exposed, partially
separated from the surrounding tissues ("mobilized"), and brought into the
scrotum. It is sutured to the scrotal tissue or enclosed in a "subdartos
pouch". The associated passage back into the inguinal canal, an inguinal
hernia, is closed to prevent reascent. In patients with intra-abdominal
maldescended testis, laparoscopy is useful to see for oneself the pelvic
structures, position of the testis and decide upon surgery (single or staged
procedure ).

Surgery becomes more complicated if the blood supply is not ample and
elastic enough to be stretched into the scrotum. In these cases, the supply
may be divided, some vessels sacrificed with expectation of adequate
collateral circulation. In the worst case, the testis must be
"autotransplanted" into the scrotum, with all connecting blood vessels cut
and reconnected (anastomosed).

17
When the testis is in the abdomen, the first stage of surgery is exploration
to locate it, assess its viability, and determine the safest way to maintain or
establish the blood supply. Multistage surgeries, or autotransplantation and
anastomosis, are more often necessary in these situations. (Brouwers,
2012)

CONCLUSION

Painting a picture of the factors that lead to maldescent of the testes is a

difficult task, as evidenced by the uncertainties noted in this review. We
have presented a list of putative risk factors in Box 1, which lists risk
factors according to the likelihood that they are associated with
cryptorchidism development. However, there are few instances in which
there is consistent evidence with respect to a given exposure; and in those
cases where evidence appears unequivocal – for example, the relationship
between cryptorchidism and gestational measures such as low birth weight
– the measured exposure actually represents exposure(s) that we don’t yet
fully understand in the cryptorchidism context. Perhaps these caveats
provide a clue as to why a concrete understanding of the aetiology of this
disease remains elusive: in a situation where myriad (and often ubiquitous)
exposures have been associated with cryptorchidism, it is likely that the
causal roots of this condition are multifactorial and highly variable between
individuals. Rather than a handful of candidate exposures being responsible
for the vast majority of cases, perhaps the relative importance of each risk
factor varies considerably between mother/son pairs depending on an
array of genetic, maternal, placental and foetal factors – all of which could
vary between regional contexts. In short, the complexity of (and mystery
18
surrounding) the aetiology of this disease is perhaps an appropriate
reflection of the complexity of the biological mechanisms that drive
testicular descent in the first place.

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