To produce a normal semen sample upon ejaculation requires the
coordination of many different events. When any one of these events
is abnormal the resulting semen sample can be compromised. Two
major categories of events are spermatogenesis/spermiogenesis
(processes that increase the number of immature germ cells and
promote the subsequent development of these primitive germ cells
into mature sperm in the testes) and ejaculation (a process that
includes penile erection, emission of sperm into the posterior
penile urethra and ejaculation of sperm out from the penile urethra).
TABLE OF CONTENTS
- Movement of the testes into the scrotum
- The testicular cells and their functions
- Puberty and the full maturation of sperm
- The course of movement for sperm upon ejaculation
- Necessary postejaculatory changes in sperm
(1) Normally testes move from the abdomen to the scrotum prior
During fetal development (inside the mother's uterus), a male
normally forms testes within the abdomen and during the last trimester
of pregnancy these testes descend into the scrotal sac. The testes
are near the inguinal crease as they move through the inguinal
canal at about 7 months gestation and the testes are normally
within the scrotal sac by delivery at term.
Hormones regulate the descent of the testes, including
(a) mullerian inhibiting factor, which is primarily responsible
for testicular movement from the initial location high in the
abdomen to the inguinal canal and
(b) testosterone, which is primarily responsible for movement
from the inguinal canal to the scrotum.
If there is failure of the testes to descend normally (called
"cryptorchid testes"), the blood and nerve supply to
the testes can be damaged. In this event, permanent damage to
the testes can result in decreased fertility. Repair of undescended
testes is ideally performed surgically (orchiopexy) within 2 years
The incidence of male fetuses born at term with undescended testes
may be as high as 3-4% (1 in 25-35), but since the majority of
these testes go on to descend on their own within the first year
of life surgery is usually delayed to allow for spontaneous recovery.
The overall incidence of cryptorchidism in adult males is only
0.3-0.4% (1 in 250-350).
It has been found that males with one undescended testis usually
have a decrease in semen quality compared to normal fertile men
that is independent of the timing of surgical repair. This suggests
that there is bilateral damage to the testes even when only one
testis is undescended. However, many men with a unilateral undescended
testis will be fertile despite a decrease in semen quality. Therefore,
treatment for infertility in these men should follow the usual
recommendations based on their semen analysis, history and physical
There is a higher incidence of testicular cancer in men with undescended
testes. The lifetime risk for development of invasive testicular
cancers is about 0.5% (1 in 200) in the USA. This risk of invasive
testicular cancer is about 5 times greater in men with a history
of undescended testes. Pre-invasive testicular cancer (carcinoma
in situ) can be detected by testicular biopsy. Since the incidence
of carcinoma in situ in a testis that was undescended is about
5% (1 in 20) it is prudent to consider biopsy for all of these
testes. Expert consultation with an experienced urologist is advised
to determine appropriate follow-up in all men with a history of
a cryptorchid testis.
(2) The human testes is composed of a number of cells with
* (A) germ stem cells (gonocytes)
Stem cells are cells that are not irreversibly differentiated
into specialized cells, are capable of dividing (increasing their
number) without limitation for the lifetime of the animal, and
which divide into daughter cells that can choose to either become
other stem cells or differentiate irreversibly into specialized
cells. Stem cells are required to replace specialized cells (such
as mature sperm cells) that cannot themselves divide.
Gonocytes continuously replenish themselves in the adult human
male, which is why a man's age does not play a very important
role in fertility. If there is a major insult to this stem cell
population, a complete lack of sperm (azoospermia) can result.
As opposed to the male situation, females are born with their
entire number of eggs already present in the ovaries (they are
not stem cells). This is the primary reason why a woman's age
is closely related to her fertility.
Germ line cells produce the next generation of gametes (sperm
in males, eggs in females) while somatic cells form the rest of
the body. Gametes are cells that are specialized for sexual fusion
resulting in an embryo.
In the human testes, the critical events that take place to form
the gonocyte population are not clearly understood. This period
of development has been extensively studied in male rodents (mostly
rats) which is considered to be an "unproven" model
for the human system. In the rat, there is an initial period of
rapid proliferation (duplication of existing cells by the process
of mitosis in which cells normally divide into identical daughter
cells to increase their number) of gonocytes prior to birth, a
subsequent arrest in proliferation until puberty, and another
period of rapid proliferation of stem cells at puberty that is
associated with the degeneration of a large number of these cells.
The final outcome is a normal adult number of stem cells.
During the quiet period between the initial expansion of cells
and puberty, rat germ cells are highly sensitive to radiation.
It would be important to understand whether this period in development
is similarly sensitive to radiation in humans, so that we could
better understand potential causes for azoospermia.
Sertoli only syndrome is a condition characterized by seminiferous
tubules that are devoid of germ cells, possibly due to abnormal
migration in the early male embryo. In this syndrome there is
little to no peritubular hyalinization (to distinguish it from
conditions like Klinefelter's syndrome where there is extensive
destruction to the tubules with sclerosis and hyalinization) and
only a slight decrease in size of the testes.
* (B) mature Sertoli cells
Sertoli cells are the testicular cells that ultimately control
Seminiferous tubules make up about 90% of the testicular volume
and are long tubes (70 cm long, tightly coiled) lined by a single
layer of Sertoli cells. At puberty, spermatogenesis is initiated
by Sertoli cells within the seminiferous tubules under the influence
of FSH and testosterone (as well as possibly several growth factors).
After initiation, testosterone alone may maintain spermatogenesis
(possibly with decreased efficiency).
Sertoli cells produce a number of proteins that are critically
important for normal testicular function. They produce (among
other proteins) (1) mullerian inhibiting factor, which acts embryonically
to cause regression of the mullerian ducts (which form the female
internal genital system) and assist testicular descent to the
level of the inguinal canal, (2) androgen binding protein, which
remains largely in the collecting ducts and the seminiferous tubules
where it concentrates testosterone in the testes at levels up
to 50 fold greater than circulating levels, and (3) inhibin, which
decreases circulating FSH concentrations
* (C) a blood testis barrier
Tight junctional complexes between Sertoli cells effectively create
an impermeable wall that divides the seminiferous tubule into
two compartments. The basal (outer) compartment is accessible
to substances within the circulation (blood) whereas the adlumenal
(inner) compartment is not accessible to substances in the blood.
As gonocytes differentiate into specialized mature sperm cells
they move across this blood testis barrier. Apparently the tight
junctions transiently unzip to allow developing spermatogonia
Once past the blood testis barrier the developing spermatogonia
begin to develop unique surface antigens (immunoreactive components
that can activate an immunologic response). If the barrier is
destroyed or damaged, such as following trauma or infection, then
the man's immune system can develop antibodies to the sperm (anti-sperm
antibodies). The antibodies can impair sperm motility (if directed
against the sperm's tail) or fertilization of an egg (if directed
against the sperm's head).
* (D) mature Leydig cells
The testes produce testosterone for male sexual development and
sperm maturation. Leydig cells are the testosterone producing
cells in the testes. The Leydig cells reside between the seminiferous
tubules within (what is called) the interstitial spaces. LH enhances
testosterone production by the Leydig cells.
Leydig cells are abundant prior to birth and in the neonatal period,
when they produce the testosterone needed for the fetal development
of male internal and external genitalia. The number of these cells
then declines to very low levels in the prepubertal years when
testosterone production is minimal. At puberty, there is a tremendous
increase in the number of Leydig cells and their testosterone
production. Pubertal testosterone is needed for spermatogenesis.
(3) At puberty, immature sperm cells (spermatogonia) develop
into highly specialized mature sperm cells (spermatozoa)
* (A) the time required for spermatogenesis in humans is about
During this time, the spermatogonia replicate (reproduce) their
DNA to acquire twice the normal amount of chromosomal material
and then in two steps (reduction and division) the DNA is reduced
to one half the normal amount in each of 4 spermatids (immature
sperm cells). In this manner, each primitive undifferentiated
sperm cell (spermatogonia) gives rise to 4 chromosomally unique
sperm cells (spermatids) that normally will become capable of
* (B) "spermiogenesis" occurs
The sperm's development from the spermatid stage to the spermatozoa
stage is referred to as "spermiogenesis." During this
time, development includes (1) formation of the acrosome, a cap
over a large area of the head of the sperm that contains a number
of enzymes that are instrumental in dissolving a path through
the shell of the egg (the zona pellucida) at the time of fertilization,
and (2) formation of the tail of the sperm, a complex structure
that contains its own energy source (called mitochondria, which
are lined up in an end to end spiral) and is responsible for sperm
(4) Mature spermatozoa leave the seminiferous tubules of the
testes to enter a series of different ducts and tubules.
* sperm travel into the epididymis
Initially spermatozoa cross the rete testis and the efferent ducts
to rapidly pass into the epididymis where they are stored.
Sperm resides in the caput or head, then the corpus or body and
finally in the cauda or tail of the epididymis. As sperm traverse
the epididymis they change significantly to
- become motile,
- change shape, and
- undergo physiologic alterations
Abnormalities in the epididymis may result in abnormal sperm motility,
sperm morphology (shape) or unexplained infertility.
The epididymis is formed from an embrologic structure called the
Wolffian duct during the first trimester of pregnancy, under the
influence of testosterone. Any genetic defect in testosterone
biosynthesis will potentially result in congenital abnormalities
in the epididymis.
In man, about 50% of spermatozoa are stored in the cauda (tail)
of the epididymis, with the average time of storage in the epididymis
between 10 and 20 days. Sperm can be damaged during epididymal
storage by elevated temperature (such as in the presence of a
varicocele), infection, or other hostile conditions. In some patients
with persistent abnormalities in the motility and shape of sperm
there is tremendous improvement in the quality of sperm with daily
ejaculation to limit the time of storage in the epididymis.
(5) Ejaculation expels the sperm
* (A) erection
Penile erection is primarily a vascular event that relies on increased
arterial flow with decreased venous flow (so that more blood collects
into the penis to produce rigidity). The changes in blood flow
are controlled by the nervous system, including the parasympathetic
and sympathetic nervous system. Research suggests that some parasympathetic
nerves may be able to respond to both penile tactile and psychic
stimulation while other sympathetic nerves may be able to respond
to predominantly psychic stimulation. Medication that affects
these nerves can affect the ability to achieve an erection.
* (B) emission
Emission is the deposition of seminal fluid into the posterior
urethra. This requires that the seminal fluid released from the
epididymis has traversed the vas deferens into the urethra. The
vas deferens is about 30cm long and initiates at the epididymis
(epididymal portion), passes through the scrotum (scrotal portion)
into the abdomen via the inguinal canal (inguinal portion) where
it then passes through the pelvis (pelvic portion) to the posterior
urethra (ampullary portion).
Emission appears to be primarily under the control of the sympathetic
nervous system. Men who have had a retroperitoneal lymph node
dissection (RLND) for testicular cancer occasionally will have
a disruption of the sympathetic nervous system, which can result
in a lack of emission and/or retrograde ejaculation into the bladder.
* (C) ejaculation
Ejaculation normally propels the seminal fluid collected in the
posterior urethra out through the penis. The bladder neck's physiologic
urinary sphincter is normally closed during emission and ejaculation
to prevent retrograde ejaculation into the bladder. This closure
of the bladder neck is predominantly controlled by the sympathetic
nervous system. Men with a history of RLND may have retrograde
ejaculation into the bladder due to disruption of the local sympathetic
(6) Ejaculated sperm becomes capable of fertilization hours
Sperm must undergo a process called "capacitation" to
become capable of fertilization (allows sperm to undergo the acrosome
reaction upon binding to the shell of the egg). Capacitation normally
occurs during the sperm's residence in the female reproductive
tract. Capacitation takes about 4-6 hours after ejaculation (whether
in the female reproductive tract or artificial media) which is
why sperm is not immediately used after ejaculation for insemination
of retrieved eggs during IVF. If the sperm is not able to live
in the pre-ovulatory cervical mucus for several hours this can
result in infertility.
The acrosome reaction is a process that allows the contents of
the acrosome to digest the shell of the egg (zona pellucida).
The acrosome covers the top two thirds of the sperm head and as
the sperm and egg meet this outer acrosomal membrane breaks down
to release digestive enzymes that assist in the penetration of
the egg. If an abnormal percentage of sperm have premature acrosome
reactions then a problem with fertilization is possible.