2. Undescended testis is the commonest genital malformation in boys.
Although the mechanism that regulates prenatal testicular descent is still
partly obscure, there is persuasive evidence that endocrine, genetic, and
environmental factors are involved.
Approximately 10% of the infertile men have a history of cryptorchidism
and orchidopexy.
Azoospermia is evident in 13% of unilateral cryptorchidism and increase
to 89% in untreated bilateral cryptorchid patients.
The risk of infertility in adulthood is more significant in patients with
bilateral undescended testes.
2
Introduction
The main risk factors for the cryptorchid testis are
infertility and testicular cancer (TC)
3. 3
In both sexes, the descent of the gonad depends on
the ligamentous gubernaculum.
Between the 7th and 12th weeks (the intra-abdominal
phase), the extrainguinal portions of the
gubernacula shorten and in males, pull the testes
down to the vicinity of the deep inguinal ring.
The testes remain in the vicinity of the deep ring from
the 3rd to the 7th month but then enter the inguinal
canal in response to renewed shortening and
migration of the gubernacula (the inguinal-scrotal
phase)
The testes remain within the subserous fascia of the
vaginal process through which they descend toward the
scrotum.
Testicular descent and maldescent
The process of testicular descent has two distinct
phases:
transabdominal and inguinal
4. 4
By the 9th month, just before normal term delivery, the testes have
completely entered the scrotal sac and the gubernaculum is reduced
to a small ligamentous
5. 5
Many undescended testicles are accompanied by patency of the
vaginal process This like the simultaneous presence of inguinal
hernia, is treated surgically during the orchidofuniculolysis
procedure.
6. Prevalence
6
Up to one third of premature boys are affected by maldescensus testis,
while about 2% to 5% of full-term boys have at least one undescended
testicle.
Short-term postnatal endogenous testosterone secretion reduces this
incidence to 1% to 2% after three months.
The pathology is bilateral in about 20% of the cases.
A birth weight below 2.5 kg and premature delivery are risk factors for
maldescent.
About 80% of undescended testes are palpable and 20% are non-palpable
Palpable undescended testes are located along the inguino-scrotal region
7. Undescended testis can be categorized on the basis of physical
examinations
7
Undescended testis : The testicle is located intra-abdominally or in the inguinal canal. It is
located in the normal descent pathway and shows normal insertion of the gubernaculum.
Cryptorchidism: The testicle is not palpable and is located intra-abdominally (retentio testis
abdominalis) or is not present (anorchia).
Ektopia testis: The testicle is located beneath the skin
superfascially, perineally, on the thigh or shaft of the penis.
The testicle shows abnormal insertion of the gubernaculum
Inguinal testicle: The testicle is palpable in the groin
(retentio testis inguinalis)
Gliding testicle: The testicle is located at the scrotal entrance or above the scrotum. It can be
drawn down into the scrotum, but immediately slides back into its initial position
Retractile (hypermobile testes): The physiological retractile (hypermobile) testicle is usually
present in the scrotum or can be effortlessly pushed down into the scrotum, it retracts on
induction of the cremasteric reflex but returns spontaneously into the scrotum. Recognizing the
retractile (hypermobile) testicle is particularly important because it does not require treatment.
8. 8
It is important to differentiate the true cryptorchidism from the retractile testis,
which is a normal finding and usually it does not require surgical treatment
The anatomical classification
of undescended testis :
Maldescended testes:
(lying somewhere along the
normal line of descent)
Ectopic testes:
(lying outside that line
Retractile testes are when, on occasion, the muscle attached to the testis (the cremasteric muscle)
pulls the testis up into the groin so that it cannot be felt or seen. If the testis can be moved back
down to the scrotum, then no further treatment is needed. Retractile testes can stay higher in the
scrotum over the years, but this usually corrects itself by puberty
9. 9
During transabdominal descent, development of the gubernaculum and
genitoinguinal ligament plays an important role.
The anti Müllerian hormone regulates the transabdominal descent of the
testes.
Induction of the gubernaculum depends on a functional Insl3 gene in mice
This gene is expressed in Leydig cells and its targeted deletion causes
bilateral cryptorchidism with free-moving testes and genital ducts
Androgens play an important role in both phases of testicular descent, while
other gene families, e.g. the homeobox (HOX) and GREAT/RXFP2 genes
(G-protein-coupled receptor affecting testis descent), are important in the
development of genital organs and may be associated with testicular
maldescent.
10. Hormonal control of testicular descent
10
Maldescent can be caused by two hormonal factors: hypogonadism and
androgen insensitivity.
Androgens and pituitary hormones clearly play essential roles in
mediating the second stage of descent.
The increasing incidence of reproductive abnormalities in male humans
can be explained by increased oestrogen exposure during gestation .
Some pesticides and synthetic chemicals act as hormonal modulators,
often possessing oestrogenic activity (xeno-oestrogens). The
oestrogenic and anti-androgenic properties of these chemicals may
cause hypospadias, cryptorchidism, reduced sperm density, and an
increased incidence of testicular tumours in animal models, via receptor-
mediated mechanisms or direct toxic effects associated with Leydig cell
dysfunction.
11. Pathophysiological effects in maldescended testes
11
Degeneration of germ cells
Relationship with fertility
Germ cell tumours
The degeneration of germ cells in maldescended testes is apparent after
the first year of life.
Degenerative changes vary, depending on the position of the testis.
During the second year, the number of germ cells declines.
In 10-45% of affected patients, the complete loss of germ cells can be
detected
12. 12
It starts during the first years after birth
In normal testes, germ cell development is an active process starting in the first
months of life when the neonatal gonocytes transform into adult dark (AD)
spermatogonia. These cells are now thought to be the stem cells useful to
support spermatogenesis. Several researches suggest that AD spermatogonia
form between 3 and 9 months of age. Not all the neonatal gonocytes transform
into AD spermatogonia; indeed, the residual gonocytes undergo involution
by apoptosis. In the undescended testes, these transformations are inhibited
leading to a deficient pool of stem cells for post pubertal spermatogenesis.
Germ cell development
Gonocyte
adult dark (AD)
spermatogonia
Adult pale(AP)
spermatogonia
B spermatgnia
Primary
spermatocytes
Data suggest that AD spermatogonia developmental cycle needs normal
testicular hormones and the optimal scrotal temperature of 33°C
13. 13
The failure of transformation of gonocytes into AD spermatogonia leads to a deficient
pool of stem cells for post pubertal spermatogenesis and infertility.
in undescended testes, germ cells loss starts at 6 months of age
It is very interesting to note that the intra-tubular carcinoma in situ (CIS) in the
second and third decade has enzyme markers similar to neonatal gonocytes as
placental alkaline phosphatase expression, suggesting that these cells, that fail to
develop in AD spermatogonia at 3–9 months of age, are the origin of cancer in
cryptorchid men.
Testiclar
cancer (TC)
14. 14
The etiology accepted for germ cell carcinoma remains unknown,
although disturbances in the microenvironment provided by the
Sertoli and Leydig cells may play an important role. In fact,
spermatogenesis is strictly controlled and depends on a succession of
signals supplied from the local environment and Leydig cells, next to
their steroidogenic function, during development express the insulin-
like-3 gene (INSL3), which is responsible for gubernaculum
maturation and testicular descent.
A specific association of mutations in INSL3 with cryptorchidism has
been described but its possible role in TC development and infertility
needs to be clarified.
Leydig
cell gubernaculum maturation
testicular descent
INSL3
15. 15
It is known that undescended testes, if untreated, lead to an
increased risk of TC, usually seminomas, arising from mutant
germ cells. TC is a solid neoplasm that has an incidence of 1%
of all cancers in men and is the most common between 20
and 30 years of life.
Boys with an undescended testis have a 20-fold higher risk
to develop a TC and about 10% of the cases of TC develop in
men with a history of cryptorchidism.
16. 16
Treatment of undescended testes
Hormonal treatment (Hormone therapy)
Surgical treatment
The goals of treatment of cryptorchidism are mainly two:
preserve fertility and reduce the risk of neoplastic disease. Last but not the least,
treatment allows the testicular self-examination for an early diagnosis and detection of
TC.
In the new guidelines, two goals of hormone therapy are pursued:
induction of descent of the retained testicle
stimulation of germ cell maturation and proliferation to contribute to
improving fertility.
Hormonal treatment with human chorionic gonadotropin (hCG) or gonadotropin-
releasing hormone (GnRH) may be initially administered for cryptorchidism because it
should promote the testicular descent.
although 15-20% of retained testes descend during hormonal treatment, one-
fifth of these re-ascend later
17. 17
The theoretical basis for its use is to stimulate the Leydig cells to produce
testosterone, inducing inguinal–scrotal testicular descent.
Potential harmful effects of hormonal treatment on the developing testes,
including apoptosis, inflammation, and reduced number of germ cells
are still under study.
In addition, there are reports which suggest that the hormonal stimulation in
infancy may be damaging to the testes.
These experimental data emphasize the possible negative outcome of hormone
therapy on germ cell line and its main action on Leydig cells. The increased synthesis
of vascular endothelial growth factor (VEGF), determined by hCG therapy also
highlights the increased cell permeability causing interstitial edema.
Side effects of hCG therapy may include enlargement of the penis (3%), growth of
genital hair, testicular enlargement, and aggressive behaviour of the child during the
treatment (1%).
18. 18
In a comparative randomized double-blind study, clinical success was observed in
6% of the boys treated with hCG and in 19% after GnRH treatment.
Increases in luteinizing hormone (LH), follicle stimulating hormone (FSH) and the
non-measurability of Mullerian inhibiting substance (MIS) are suggestive of
anorchia. Elevated gonadotropins and a negative intramuscular human
chorionic gonadotropin (hCG) stimulation test without evidence of testosterone
production reinforce this assumption. Final proof of anorchia, however, is provided
by surgical exploration.
For bilateral nonpalpable testicles, a pediatric endocrinological assessment is
indicated, among other things in order to rule out other syndromes.
19. 19
Stimulated testosterone values are compared before and 32 hours after an
intramuscular dose of 5000 IU hCG. If functional testicular tissue is present, the
testosterone values increase to twice the baseline value after hCG administration.
Increased baseline FSH and LH values associated with an absent testosterone
increase after stimulation demonstrates the absence of functional testicular
tissue. With a normal phenotype and normal 46-XY karyotype, the diagnosis
anorchia can be regarded as certain.
The hCG stimulation test
is used to demonstrate the
presence of functional
testicular tissue. It is
therefore only useful in
bilateral cryptorchidism.
20. 20
The following factors increase child’s chance of having undescended
testes:
Prematurity
Low birth weight
Twin gestation
Down syndrome (fetus) or other chromosomal abnormality
Gestational diabetes mellitus
Prenatal alcohol exposure
Hormonal abnormalities (fetus)
Toxic exposures in the mother
Mother younger than 20
A family history of undescended testes
Risk Factors
21. 21
Surgical treatment
The purpose of the operation is to search for the retracted testicle and, after
adequate orchidolysis, to achieve tension-free transfer to and fixation in
the scrotum. For intra-abdominal testicle, this is possible using either an
open surgical or laparoscopic technique.
An incision is made into the abdomen, the
site of the undescended testicle, and
another is made in the scrotum (A). The
testis is detached from surrounding tissues
(B) and pulled out of the abdominal incision
attached to the spermatic cord (C). The
testis is then pulled down into the scrotum
(D) and stitched into place (E).
22. 22
The reasons for performing an operation include:
Fertility: men with undescended testicles have a higher rate of infertility
Hernia:An undescended testicle is associated with a connection
between the abdomen and scrotum called a “hernia”. During repair of
the testicle, the hernia sac is closed
Tumor: Undescended testicles have a higher risk of developing a
testicular tumor, periodically examine the testicle. This is very important
for early detection of tumors.
Torsion: Undescended testicles have a higher risk of spontaneously
twisting and stopping the blood flow to the testicle
One complication of orchidopexy is testicular atrophy. Division of the
testicular vessels and/or postoperative swellings and infections can result
in testicular ischemia and cause (partial) atrophy of the testicle
24. 24
High scrotal unilateral cryptorchid gliding testis. Shown is a biopsy specimen from a
17-year-old Patient. The biopsy specimen shows a maturation arrest of
spermatogenesis ( asterisks ). The other tubules are lined by Sertoli cells only
25. 25
High scrotal unilateral cryptorchid testis. The seminiferous tubules are lined by
Sertoli cells and degenerated spermatogonia with some maturation to the
primary spermatocyte stage ( asterisk ).
26. 26
high scrotal unilateral cryptorchid gliding testis from a 20-year-old man. This sample allows
comparison of immature ( stars ) with mature (crosslet ) Sertoli cells. The immature cells within
nodules are smaller; they contain minor nuclei without a clear nucleolar complex and have
scanty cytoplasm. Hyaline deposits ( H ) in the middle of the nodules may originate from an
increased production of basement membrane material. In contrast, mature Sertoli cells have
a well-de fi ned nucleolar complex and plentiful cytoplasm.
27. 27
high scrotal unilateral cryptorchid gliding testis in a 19-year-old man. The
cytoplasm of the Sertoli cells is granulated. The nuclei of these cells may be
wrinkled ( arrowheads )
28. 28
Biopsy specimen from a 21-year-old man with a high scrotal unilateral cryptorchid
gliding testis. The tubule is lined by mature Sertoli cells only. In the Sertoli cell
cytoplasm, many slender spindle-shaped Charcot-Böttcher crystals are present (
arrowheads ). The tunica propria is thickened( arrow )