Sperm production: what normally occurs?
Production of 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.
Processes that increase the number of immature germ cells and promote the subsequent development of these primitive
germ cells into mature sperm are called "spermatogenesis and spermiogenesis."
"Ejaculation" releases mature sperm through a series of events including penile erection, emission of sperm into
the posterior penile urethra and ejaculation of sperm out from the penile urethra.
(1) Normally testes move from the abdomen to the scrotum prior to birth.
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.
Available Case Reports:
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 of age.
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.
There is a higher incidence of testicular cancer in men with undescended testes. The overall 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 are composed of a number of cells with specific functions.
(A) germ stem cells (gonocytes)
In the normal male testes there are gonocytes (primitive germ stem cells) that can divide (without limitation) into
additional (daughter) cells which can then choose to become other (immature) stem cells (continuously replenishing the supply
of this type of cell) or differentiate (specialize) into mature sperm cells. Fresh mature sperm cells can be produced as long
as there is a supply of gonocytes within the testes. In contrast, females are born with all of their eggs (partially matured
within the ovaries) and these eggs are incapable of dividing into additional egg cells. The presence of gonocytes within the
male testes is the primary reason why a man's fertility does not decrease significantly with age.
(B) mature Sertoli cells
Sertoli cells are important testicular cells that ultimately control spermatogenesis.
Seminiferous tubules are long tubes (70 cm long and tightly coiled) that are lined by a single layer of Sertoli cells and
make up about 90% of the testicular volume. 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 compartment is accessible to substances within the (blood)
circulation whereas the adlumenal 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 to cross. 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 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 which is required 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.
Available Case Reports:
(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 74 days.
During spermatogenesis, the maturing sperm cells replicate (reproduce) their DNA to acquire twice the normal amount of
chromosomal material. Following this replication of DNA the primitive (undifferentiated) sperm cells (spermatogonia) divide
two times so that each sperm cell results in the formation of four (4) immature sperm cells (called spermatids).
Each spermatid has one half the normal amount of chromosome material (normal human cells have 23 pairs of chromosomes,
each normal spermatid has only one of the pair for each of the 23 chromosomes). When a mature sperm cells ultimately unites
with a mature egg (which also has only one of the pair for each of the 23 chromosomes) the resulting fertilized egg then has
23 pairs of chromosomes (one of each pair from the "father" and one of each pair from the "mother").
Available Case Reports:
(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) and is
responsible for sperm motility.
(4) Mature spermatozoa leave the seminiferous tubules of the testes to enter a series of different ducts and tubules.
(A) 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 embryologic 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
Available Case Reports:
(5) ejaculation expels the sperm
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.
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.
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 nerves.
(6) Ejaculated sperm becomes capable of fertilization hours after ejaculation
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 the 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.