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Women who are fertile experience a natural period of fertility before and during
ovulation, and they are naturally infertile during the rest of the menstrual cycle. Fertility
awareness methods are used to discern when these changes occur by tracking changes in
cervical mucus or basal body temperature.
Infertility is the failure of a couple to become pregnant after one year of regular,
unprotected intercourse. In both men and women the fertility process is complex.
Infertility affects about 10% of all couples. Even under ideal circumstances, the
probability that a woman will get pregnant during a single menstrual cycle is only about
30%. And, when conception does occur, only 50 - 60% of pregnancies advance beyond
the 20th week. (The inability of a woman to produce a live birth because of abnormalities
that cause miscarriages is called infecundity and is not discussed in detail in this report.)
About a third of infertility problems are due to female infertility, and another third are
due to male infertility. In the remaining cases, infertility affects both partners or the cause
is unclear. Although this report specifically addresses infertility in women, it is equally
important for the male partner to be tested at the same time.
MALE INFERTILITY OVERVIEW
Approximately 15% of couples attempting their first pregnancy meet with failure. Most
authorities define these patients as primarily infertile if they have been unable to achieve
a pregnancy after one year of unprotected intercourse. Conception normally is achieved
within twelve months in 80-85% of couples who use no contraceptive measures, and
persons presenting after this time should therefore be regarded as possibly infertile and
should be evaluated. Data available over the past twenty years reveal that in
approximately 30% of cases pathology is found in the man alone, and in another 20%
both the man and woman are abnormal. Therefore, the male factor is at least partly
responsible in about 50% of infertile couples.
Important issues related to the evaluation of the male factor include the most appropriate
time for the male evaluation, the most efficient format for a comprehensive male exam,
and definition of rationale and effective medical and surgical regimens in the treatment of
these disorders. It is extremely important in the evaluation of infertility to consider the
couple as a unit in evaluation and treatment and to proceed in a parallel investigative
manner until a problem is uncovered. It has been shown that the longer a couple remains
subfertile, the worse their chance for an effective cure. Many couples experience
significant apprehension and anxiety after only a few months of failure to conceive.
Unduly prolonged unprotected intercourse should not be advocated before a workup of
the man is instituted. Initial screening of the man should be considered whenever the
patient presents with the chief complaint of infertility. This initial evaluation should be
rapid, non-invasive and cost effective. Of interest is the fact that pregnancy rates of up to
50% have been reported when only the woman has been investigated and treated even
when the man was found to have moderately severe abnormalities of semen quality.
MALE REPRODUCTIVE PHYSIOLOGY
The hypothalamus is the integrative center of the reproductive axis and receives messages
from both the central nervous system and the testes to regulate the production and
secretion of gonadotropin releasing hormone (GnRH). Neurotransmitters and
neuropeptides have both inhibitory and stipulatory influence on the hypothalamus. The
hypothalamus releases GnRH in a pulsatile nature which appears to be essential for
stimulating the production and release of both luteinizing hormone (LH) and follicle
stimulating hormone (FSH). Interestingly and paradoxically, after the initial stimulation
of these gonadotropins, the exposure to constant GnRH results in inhibition of their
release. LH and FSH are produced in the anterior pituitary and are secreted episodically
in response to the pulsatile release of GnRH. LH and FSH both bind to specific receptors
on the Leydig cells and Sertoli cells within the testis. Testosterone, the major secretory
product of the testes, is a primary inhibitor of LH secretion in males. Testosterone may be
metabolized in peripheral tissue to the potent androgen dihydrotestosterone or the potent
estrogen estradiol. These androgens and estrogens act independently to modulate LH
secretion. The mechanism of feedback control of FSH is regulated by a Sertoli cell
product called inhibin. Decreases in spermatogenesis are accompanied by decreased
production of inhibin and this reduction in negative feedback is associated with reciprocal
elevation of FSH levels. Isolated increased levels of FSH constitute an important,
sensitive marker of the state of the germinal epithelium.
Prolactin also has a complex inter-relationship with the gonadotropins, LH and FSH. In
males with hyperprolactinemia, the prolactin tends to inhibit the production of GnRH.
Besides inhibiting LH secretion and testosterone production, elevated prolactin levels
may have a direct effect on the central nervous system. In individuals with elevated
prolactin levels who are given testosterone, libido and sexual function do not return to
normal as long as the prolactin levels are elevated.
THE TESTES
Leydig; Cells
Testosterone is secreted episodically from the Leydig cells in response to LH pulses and
has a diurnal pattern, with the peak level in the early morning and the trough level in the
late afternoon or early evening. In the intact testis, LH receptors decrease or down-
regulate after exogenous LH administration. Large doses of GnRH or its analogs can
reduce the numbers of LH receptors and therefore inhibit LH secretion. This has been
applied clinically to cause medical castration in men with prostate cancer. Estrogen
inhibits some enzymes in the testosterone synthetic pathway and therefore directly effects
testosterone production. There also appears to be an intratesticular ultra short loop
feedback such that exogenous testosterone will override the effect of LH and inhibit
testosterone production. In normal males, only 2% of testosterone is free or unbound.
44% is bound to testosterone-estradiol-binding globulin or TeBG, also called sex
hormone-binding globulin. 54% of testosterone is bound to albumin and other proteins.
These steroid-binding proteins modulate androgen action. TeBG has a higher affinity for
testosterone than for estradiol, and changes in TeBG alter or amplify the hormonal
milieu. TeBG levels are increased by estrogens, thyroid administration and cirrhosis of
the liver and may be decreased by androgens, growth hormone and obesity. The
biological actions of androgens are exerted on target organs that contain specific
androgen receptor proteins. Testosterone leaves the circulation and enters the target cells
where it is converted to the more potent androgen dihydrotestosterone by an enzyme 5-
alpha-reductase. The major functions of androgens in target tissues include 1) regulation
of gonadotropin secretion by the hypothalamic-pituitary axis; 2) initiation and
maintenance of spermatogenesis; 3) differentiation of the internal and external male
genital system during fetal development; and 4) promotion of sexual maturation at
puberty.
Somniferous Tubules
The somniferous tubules contain all the germ cells at various stages of maturation and
their supporting Sertoli cells. These account for 85-90% of the testicular volume. Sertoli
cells are a fixed-population of non-dividing support cells. They rest on the basement
membrane of the seminiferous tubules. They are linked by tight junctions. These tight
junctions coupled with the close approximation of the myoid cells of the peritubular
contractile cell layers serve to form the blood-testis barrier. This barrier provides a unique
microenvironment that facilitates spermatogenesis and maintains these germ cells in an
immunologically privileged location. This isolation is important because spermatozoa are
produced during puberty, long after the period of self-recognition by the immune system.
If these developing spermatozoa were not immunologically protected, they would be
recognized as foreign and attacked by the body's immune system. Sertoli cells appear to
be involved with the nourishment of developing germ cells as well as the phagocytosis of
damaged cells. Spermatogonia and young spermatocytes are lower down in the basal
compartment of the seminiferous tubule, whereas mature spermatocytes and spermatids
are sequestered higher up in the adluminal compartment.
The germinal cells or the spermatogenic cells are arranged in an orderly manner from the
basement membrane up to the lumen. Spermatogonia lie directly on the basement
membrane, and next in order, progressing up to the lumen, are found the primary
spermatocytes, secondary spermatocytes and spermatids. There are felt to be 13 different
germ cells representing different stages in the developmental process.
Spermatogenesis is a complex process whereby primitive stem cells or spermatogonia,
either divide to reproduce themselves for stem cell renewal or they divide to produce
daughter cells that will later become spermatocytes. The spermatocytes eventually divide
and give rise to mature cell lines that eventually give rise to spermatids. The spermatids
then undergo a transformation into spermatozoa. This transformation includes nuclear
condensation, acrosome formation, and loss of most of the cytoplasm, development of a
tail and arrangement of the mitochondria into the middle piece of the sperm which
basically becomes the engine room to power the tail. Groups of germ cells tend to
develop and pass through spermatogenesis together. This sequence of developing germ
cells is called a generation. These generations of germ cells are basically in the same
stage of development. There are six stages of seminiferous epithelium development. The
progression from stage one through stage six constitutes one cycle. In humans the
duration of each cycle is approximately 16 days and 4.6 cycles are required for a mature
sperm to develop from early spermatogonia. Therefore, the duration of the entire
spermatogenic cycle in humans is 4.6 cycles times 16 days equals 74 days.
An intimate structural and functional relationship exists between the two separate
compartments of the testis, i.e. the seminiferous tubule and the interstitium between the
tubules. LH affects spermatogenesis indirectly in that it stimulates androgenous
testosterone production. FSH targets Sertoli cells. Therefore, testosterone and PSH are
the hormones that are directed at the seminiferous tubule epithelium. Androgen-binding
protein which is a Sertoli cell product carries testosterone intracellularly and may serve as
a testosterone reservoir within the seminiferous tubules in addition to transporting
testosterone from the testis into the epididymal tubule. The physical proximity of the
Leydig cells to the seminiferous tubules and the elaboration by the Sertoli cells of
androgen-binding protein, cause a high level of testosterone to be maintained in the
microenvironment of the developing spermatozoa. The hormonal requirements for
initiation of spermatogenesis appear to be independent of the maintenance of
spermatogenesis. For spermatogenesis to be maintained like for instance after a pituitary
obliteration, only testosterone is required.
Transport-Maturation-Storage of Sperm
Although the testis is responsible for sperm production, the epididymis is intimately
involved with the maturation, storage and transport of spermatozoa. Testicular
spermatozoa are non-motile and were felt to be incapable of fertilizing ova. Spermatozoa
gain progressive motility and fertilizing ability after passing through the epididymis. The
coiled seminiferous tubules terminate within the rete testis, which in turn coalesces to
form the ductuli efferentes. These ductuli efferentes conduct testicular fluid and
spermatozoa into the head of the epididymis. The epididymis consists of a fragile single
convoluted tubule that is 5-6 meters in length. The epididymis is divided into the head,
body, and tail. Although epididymal transport time varies with age and sexual activity,
the estimated transit time of spermatozoa through the epididymis in healthy males is
approximately four days. It is during the period of maturation in the head and body of the
epididymis that the sperm develop the increased capacity for progressive motility and
also acquire the ability to penetrate oocytes during fertilization. The epididymis also
serves as a reservoir or storage area for sperm. It is estimated that the extragonadal sperm
reservoir is 440 million spermatozoa and that more than 50% of these are located in the
tail of the epididymis. The sperm that are stored in the tail of the epididymis enter the vas
deferens which is a muscular duct 30-35 cm in length. The contents of the vas are
propelled by peristaltic motion into the ejaculatory duct. Sperm are then transported to
the outside of the male reproductive tract by emission and ejaculation.
During emission, secretions from the seminal vesicles and prostate are deposited into the
posterior urethra. Prior to ejaculation peristalsis of the vas deferens and bladder neck
occur under sympathetic nervous control. During ejaculation, the bladder neck tightens
and the external sphincter relaxes with the semen being propelled through the urethra via
rhythmic contractions of the perineal and bulbourethral muscles. It is true that the first
portion of the ejaculate contains a small volume of fluid from the vas deferens which is
rich in sperm. The major volume of the seminal fluid comes from the seminal vesicles
and secondarily the prostate. The seminal vesicles provide the nourishing substrate
fructose as well as prostaglandins and coagulating substrates. A recognized function of
the seminal plasma is its buffering effect on the acidic vaginal environment. The
coagulum formed by the ejaculated semen liquefies within 20 to 30 minutes as a result of
prostatic proteolytic enzymes. The prostate also adds zinc, phospholipids, spermine, and
phosphatase to the seminal fluid. The first portion of the ejaculate characteristically
contains most of the spermatozoa and most of the prostatic secretions, while the second
portion is composed primarily of seminal vesicle secretions and fewer spermatozoa.
THE FEMALE REPRODUCTIVE SYSTEM
The primary organs and structures in the reproductive system are:
• The uterus is a pear-shaped organ located between the bladder and lower
intestine. It consists of two parts, the body and the cervix.
• When a woman is not pregnant the body of the uterus is about the size of a fist,
with its walls collapsed and flattened against each other. During pregnancy the
walls of the uterus are pushed apart as the fetus grows.
• The cervix is the lower portion of the uterus. It has a canal opening into the
vagina with an opening called the os, which allows menstrual blood to flow out of
the uterus into the vagina.
• Leading off each side of the body of the uterus are two tubes known as the
fallopian tubes. Near the end of each tube is an ovary.
• Ovaries are egg-producing organs that hold 200,000 - 400,000 follicles (from
folliculus, meaning "sack" in Latin). These cellular sacks contain the materials
needed to produce ripened eggs, or ova.
• The inner lining of the uterus is called the endometrium. During pregnancy, it
thickens and becomes enriched with blood vessels to house and support the
growing fetus. If pregnancy does not occur, the endometrium is shed as part of the
menstrual flow. Menstrual flow also consists of blood and mucus from the cervix
and vagina.
The uterus is a hollow muscular organ located in the female pelvis between the bladder
and rectum. The ovaries produce the eggs that travel through the fallopian tubes. Once
the egg has left the ovary it can be fertilized and implant itself in the lining of the uterus.
The main function of the uterus is to nourish the developing fetus prior to
birth.Reproductive Hormones. The hypothalamus (an area in the brain) and the pituitary
gland regulate the reproductive hormones.
The pituitary gland is often referred to as the master gland because of its important role in
many vital functions, many of which require hormones. In women, six key hormones
serve as chemical messengers that regulate the reproductive system:
• Estrogen, progesterone, and the male hormone testosterone are secreted by the
ovaries at the command of FSH and LH and complete the hormonal group
necessary for reproductive health.
Ovulation. The process leading to fertility is very intricate. It depends on the healthy
interaction of the reproductive organs and hormone systems in both the male and female.
In addition, reproduction is limited by the phases of female fertility. Nevertheless, this
process results in conception within a year for about 80% of couples. Only 15% conceive
within a month of their first attempts, however, and about 60% succeed after 6 months.
A woman's ability to produce children occurs after she enters puberty and begins to
menstruate. The process of conception is complex:
Ovulatory disorders are one of the most common reasons why women are unable to
conceive, and account for 30% of women's infertility. Fortunately, approximately 70%
of these cases can be successfully treated by the use of drugs such as Clomiphene and
Menogan/Repronex. The causes of failed ovulation can be categorized as follows:
The hypothalamus is the portion of the brain responsible for sending signals to the
pituitary gland, which, in turn, sends hormonal stimuli to the ovaries in the form of
FSH and LH to initiate egg maturation. If the hypothalamus fails to trigger and
control this process, immature eggs will result. This is the cause of ovarian failure in
20% of cases.
The pituitary's responsibility lies in producing and secreting FSH and LH. The
ovaries will be unable to ovulate properly if either too much or too little of these
substances is produced. This can occur due to physical injury, a tumor or if there
is a chemical imbalance in the pituitary.
Physical damage to the ovaries may result in failed ovulation. For example, extensive,
invasive, or multiple surgeries, for repeated ovarian cysts may cause the capsule of the
ovary to become damaged or scarred, such that follicles cannot mature properly and
ovulation does not occur. Infection may also have this impact.
This presents a rare and as of yet unexplainable cause of an ovulation. Some women
cease menstruation and begin menopause before normal age. It is hypothesized that their
natural supply of eggs has been depleted or that the majority of cases occur in extremely
athletic women with a long history of low body weight and extensive exercise. There is
also a genetic possibility for this condition.
(4) Follicle Problems
(1) Infection
Caused by both bacteria and viruses and usually transmitted sexually, these infections
commonly cause inflammation resulting in scarring and damage. A specific example is
Hydrosalpnix, a condition in which the fallopian tube is occluded at both ends and fluid
collects in the tube.
The most common of these are appendicitis and colitis, causing inflammation of the
abdominal cavity which can affect the fallopian tubes and lead to scarring and blockage.
This is an important cause of tubal disease and damage. Pelvic or abdominal surgery can
result in adhesions that alter the tubes in such a way that eggs cannot travel through them.
This is a pregnancy that occurs in the tube itself and, even if carefully and successfully
overcome, may cause tubal damage and is a potentially life-threatening condition.
In rare cases, women may be born with tubal abnormalities, usually associated with
uterus irregularities.
ENDOMETRIOSIS
ADDITIONAL FACTORS
• At least 10% of all cases of female infertility are caused by an abnormal uterus.
Conditions such as fibroid, polyps, and adenomyosis may lead to obstruction of
the uterus and Fallopian tubes.
• Congenital abnormalities, such as septate uterus, may lead to recurrent
miscarriages or the inability to concei Approximately 3% of couples face
infertility due to problems with the femaleís cervical mucus. The mucus needs to
be of a certain consistency and available in adequate amounts for sperm to swim
easily within it.
• The most common reason for abnormal cervical mucus is a hormone imbalance,
namely too little estrogen or too much progesterone.
(2) Behavioral Factors:
It is well-known that certain personal habits and lifestyle factors impact health; many of
these same factors may limit a couple's ability to conceive. Fortunately, however, many
these variables can be regulated to increase not only the chances of conceiving but also
one's overall health.
Optimal reproductive functioning requires both proper diet and appropriate levels
of exercise. Women who are significantly overweight or underweight may have
difficulty becoming pregnant.
• Smoking
Cigarette smoking has been shown to lower sperm counts in men and increases
the risk of miscarriage, premature birth, and low-birth-weight babies for women.
Smoking by either partner reduces the chance of conceiving with each cycle,
either naturally or by IVF, by one-third.
• Alcohol
Alcohol intake greatly increases the risk of birth defects for women and, if in high
enough levels in the mother’s blood, may cause Fetal Alcohol Syndrome.
Alcohol also affects sperm counts in men.
• Drugs
Drugs, such as marijuana and anabolic steroids, may impact sperm counts in
men. Cocaine use in pregnant women may cause severe retardations and kidney
problems in the baby and is perhaps the worst possible drug to abuse while
pregnant. Recreational drug use should be avoided, both when trying to conceive
and when pregnant.
• Lead
• Ethylene Oxide
• Dibromochloropropane (DBCP)
Handling the chemicals found in pesticides, such as DBCP, can cause ovarian
problems, leading to a variety of health conditions, like early menopause, that
may directly impact fertility.
CAUSES OF MALE INFERTILITY
Noonan's Syndrome is the male counterpart of Turner's Syndrome (X0), and these
individuals typically have similar features i.e. short stature, web neck, low-head ears,
cubitus valgus, ocular abnormalities and cardiovascular abnormalities. Most males with
Noonan's Syndrome have cryptorchidism and diminished spermatogenesis and are
infertile. Those with diminished testicular function will have elevated serum FSH and LH
levels. They demonstrate on chromosomal analysis a sex chromosome abnormality such
as X0/XY mosaicism. There is no treatment for their infertility.
Patients with myotonic dystrophy suffer from delayed muscle relaxation after initial
contraction. The major clinical features also include lenticular opacities, frontal baldness
and testicular atrophy. Inheritance is autosomal dominant and the expression is variable
though 80% will develop testicular atrophy. Pubertal development is usually normal and
testicular damage occurs later in adult life. Leydig cell function remains normal and there
is no gynecomastia.
Sertoli-cell-only syndrome or germinal cell aphasia may have several causes including
congenital absence of the germ cells, genetic defects, or androgen resistance. Upon
testicular biopsy there will be complete absence of germinal elements. Clinical findings
include azoospermia in association with normal virilization, testes of normal consistency
but slightly smaller in size, and no gynecomastia. Testosterone and LH levels are normal
but FSH levels are usually elevated. Sometimes in patients who have had other testicular
disorders like mumps, cryptorchidism or radiation/toxin damage, the seminiferous
tubules may also contain only Sertoli cells, but in these men the testes are small and the
histologic pattern is not as uniform. These patients are more likely to have severe
sclerosis and hyalinization as prominent features as well. There is no treatment for their
infertility.
Gonadotoxins like drugs and radiation can effect the germinal epithelium because it is a
rapidly dividing tissue and susceptible to interference of cell division. Cancer
chemotherapy has a dose-dependent effect on testicular germinal epithelium. The
germinal epithelium appears to be more resistant to toxic drugs before puberty than in
adulthood. The alkylating agents like chiromancies, cyclophosphamide and nitrogen
mustard are particular toxic to the testes. In some patients, cryopreservation of semen can
be performed before cancer chemotherapy is begun. Cyproterone, ketoconazole,
spirolactone and alcohol all interfere with testosterone synthesis. Cimetidine is a
testosterone antagonist, blocking peripheral testosterone action. These men will often
present with gynecomastia and have decreased sperm counts.
Recreational drugs like marijuana, heroin, and methadone are associated with lower
serum testosterone levels without a concomitant elevation in LH levels. This suggests a
central abnormality as well as a testicular defect. Certain pesticides like
dibromochloropropane have been found to impair testicular function in men. Germ cells
are particularly sensitive to radiation while the Leydig cells are relatively resistant. At
exposures below 600 rads, germ cell damage is reversible. Above this level of exposure
though permanent damage is likely. Recovered spermatogenesis may take up to 2-3 years
even in men who receive low doses of radiation. Elevated FSH levels reflect the impaired
spermatogenesis, with return to normal once the testes recover.
About 15-25% of adult men who contract mumps can develop orchitis which is more
commonly unilateral though bilateral involvement occurs in about 10% of affected men.
Testicular atrophy can develop within 1 to 6 months or may take years. Fewer than one-
third of men with bilateral orchitis recover normal semen parameters.
The exposed position of the testicles makes them susceptible to trauma and subsequent
atrophy. Iatrogenic injury may occur during inguinal surgery and interfere with testicular
blood supply or damage the vas deferens.
Systemic diseases like renal failure resulting in uremia in males is associated with
decreased libido, impotence and altered spermatogenesis and gynecomastia. LH and FSH
levels are elevated and testosterone levels are decreased. The cause of hypogonadism in
uremia is probably multifactorial. It has been found that serum prolactin levels are
elevated in one-fourth of the patients. An excess in estrogen may be contributory. Anti-
hypertensive drugs and uremic neuropathy may also play a role in uremic impotence and
hypogonadism. After successful renal transplantation, uremic hypogonadism improves. A
large percentage of males with cirrhosis of the liver have testicular atrophy, impotence
and gynecomastia. Testosterone levels are decreased. Estradiol is increased as a result of
decreased hepatic extraction of androgens with increased conversion to estrogen
peripherally. LH and FSH levels are only moderately elevated relative to the low serum
testosterone levels. Ethanol also acutely reduces testosterone levels by inhibiting
testicular testosterone synthesis. Many men with sickle cell disease have evidence of
hypogonadism. Even though LH and FSH levels may be variable, testosterone levels are
low. Hypogonadism of sickle cell disease is likely secondary to a mixture of testicular
and pituitary-hypothalamic causes.
Rare heredity disorders due to enzymatic defects can result in defective testosterone
synthesis and are associated with an adequate virilization that is evident at birth as
ambiguous genitalia. Several forms of androgen resistance result in under
masculinization and infertility in males with otherwise normally developed external
genitalia. Diagnosis is made by the finding of abnormal androgen receptors in a culture of
genital skin fiberblasts. Characteristically, there is an elevation testosterone and LH
levels. Proof of this is costly and there is no treatment for their infertility.
A scrotal varicocele is the most common causative finding in infertile men. It results
from backflow of blood secondary to incompetent or absent valves in the spermatic veins.
This valvular deficiency combined with the long vertical course of the internal spermatic
vein on the left side, leads to the formation of most varicoceles on the left side (90%).
Varicoceles are not as commonly seen on the right side because of the oblique course of
the right internal spermatic vein from the vena cava. A unilateral right-sided varicocele
suggests venous thrombosis/tumor or situs inversus. Newer diagnostic tests have shown
the incidence of bilateral varicoceles to be greater than 40%. The incidence of varicoceles
in the adult male population is approximately 20% and in the infertile population
approximately 40%. 50% of men with varicoceles will have impaired semen quality, but
many men varicoceles are fertile. To explain the abnormalities in spermatogenesis with
varicocele, the following theories have been proposed:
Recent experimental evidence has demonstrated bilateral increase in both testicular blood
flow and temperature with altered spermatogenesis. Unfortunately, at least 25-40% of
infertile men have idiopathic infertility for which no cause can be identified. More
known causes will be discovered hopefully as knowledge of male reproductive
physiology expands.
Acquired disorders of sperm transport are usually due to bacterial infections which may
acutely or chronically involve the epididymis with subsequent scarring and obstruction.
Apart from vasectomy, the vas may accidentally be ligated during hernia repair,
orchiopexy, and even during varicocelectomy.
Functional obstruction of sperm transport results from neuropathic insults like injuries
to the sympathetic nerves during retroperitoneal lymph node dissection or pelvic surgery.
This may cause lack of peristalsis of the vas deferens with resultant lack of emission
and/or failure of the bladder neck to close at the time of ejaculation leading to retrograde
ejaculation. Diabetic males with autonomic neuropathy frequently present with both
erectile dysfunction and/or retrograde ejaculation. Spinal cord injury can result in
paraplegia or quadriplegic with resultant erectile dysfunction and lack of emission and
ejaculation. There are many medications such as tranquilizers, antidepressants, and
antihypertensives that may interfere with the sympathetic nervous system as well.
DISORDERS OF SPERM MOTILITY OR
FUNCTION
Disorders of sperm motility and function exist secondary to problems that include
congenital defects of the sperm tail, maturation defects and immunologic defects.
Immotile cilia syndrome is a group of disorders characterized by immotility or poor
motility of spermatozoa tie. Kartagenerss Syndrome). In these disorders, testicular biopsy
is normal and the sperm count adequate but sperm motility is either markedly reduced or
absent. The defective structural abnormality leading to impairment of both the cilia and
spermatozoa is seen only with the electron microscope. The defects known to cause
immotile cilia syndrome include absent dynein arms, short or absent spokes with no
central sheath and missing central microtubules. Motility problems may also be
associated with a deficiency of the protein carboxylmethylase in the tail of the sperm.
Normal sperm counts with poor motility following vasectomy reversal may be a result of
epididymal dysfunction. Chronic intratubular pressure following vasectomy may have a
deleterious effect on the epididymis such that spermatozoa may not gain their usual
maturation and capacity for motility. Breakdown of the blood-testes barrier by infection,
trauma or operation allows sensitization of the spermatozoa antigens. Sperm antibodies
may be a relative cause of infertility in about 3-7% of infertile males. Immunity does not
appear to be an all-or-none phenomenon but may contribute to reduced fertility potential.
Infections. High concentrations of gram-negative bacteria like E-coli in the semen can
impair sperm motility. Sexually transmitted organisms such as chlamydia trichomatous,
mycoplasma hominis and ureaplasma urealyticulum have rarely been implicated in
reproductive failure. In both animals and humans, there is no convincing evidence to
support the use of routine cultures or empiric therapy in asymptomatic infertile males.
Sexual dysfunction has been reported in up to 20% of infertile males. Decreased sexual
drive, erectile dysfunction, premature ejaculation and failure of intromission are all
potentially correctable causes of reproductive failure. Decreasing libido and erectile
dysfunction may reflect low serum testosterone levels with an organic cause.
Performance anxiety is also often reported and often abated with reassurance.
DIAGNOSTIC TESTING
Semen Analysis
although semen analysis is not a test of fertility, a carefully performed semen analysis is a
highly predictive indicator of the functional status of the male reproductive hormonal
cycle, spermatogenesis and the patency of the reproductive tract. The initiation of a
pregnancy is the only true measure of fertility and is a couple-related phenomenon. One
must keep in mind that normal values have been difficult to determine for fertile men in
their reproductive years. Clinical studies of infertile patients have established "limits of
adequacy" below which the chance of initiating a pregnancy becomes more difficult.
These parameters are not absolute because some fertile men may have values below these
"limits of adequacy". Conversely, infertile men may have normal semen parameters by
standard analysis techniques because standard evaluation does not assess the functional
integrity of the sperm. The World Health Organization Laboratory Manual for
Examination of Human Semen and Semen-Cervical Mucous Interactions is highly
recommended for technical details.
Most specialists collect at least three specimens in which the seminal parameters are
within 20% of each other before establishing a baseline for semen quality. The semen
specimen is best obtained by masturbation after a two to three day period of abstinence.
The specimen should be assessed within 1-2 hours of collection. Samples obtained by
coitus interruptus or from silastic condoms devoid of spermatocidal agents are less
desirable but satisfactory. Therefore, collection at the site of analysis is ideal. Besides
laboratory error, there are variations in sperm density, motility and morphology among
multiple samples from a given man. Abstinence intervals give s large source of
variability. With each day of abstinence (up to one week) semen volume increases by 0.4
cc, sperm concentration by 10-15 million per cc, and total sperm count by 50-90 million.
Sperm motility and morphology appear to be unaffected by 5-7 days of abstinence, but
longer periods lead to impaired motility. Interpretation of semen analysis must take into
consideration the variations between samples that exist in individuals. The minimum
number of specimens to define good or poor quality of semen is three samples over a 6-8
week interval with a consistent period of abstinence of 2-3 days. In a longitudinal
analysis of semen from both fertile and infertile men, it was found that 97% of men with
initial good sperm concentration would continue to show good density after as many as 3-
6 specimens. Those rated poor at first also remained poor in future visits. For those rated
equivocal, first visit was of little value and at least three visits were needed to obtain
stability.
Semen volume must be taken into consideration assessing total sperm production by the
testes. Semen volume per se, however, effects fertility only when it falls below 1.5 cc due
to the inadequate buffering of vaginal acidity or when the volume is greater than 5 cc.
Low volumes may be associated with incomplete collection, retrograde ejaculation,
ejaculatory duct obstruction, or androgen deficiency. For most clinicians, a sperm
concentration of less than 20 million per cc is the lower limit of normal. Sperm motility is
the single most important measure of semen quality and can be a compensatory factor in
men with low sperm counts.
Sperm motility is usually rated in two ways: the number of motile sperm as a percentage
of the total, and the quality of forward progressive sperm movement i.e., how fast and
how straight the sperm swims. The degree of forward progression is a classification based
on the pattern displayed by the majority of motile sperm. It ranges from zero (no
movement) to 4 (excellent forward progression). Typically, you want to see at least 50%
of the sperm with good forward progression. Microscopic evaluation of the liquefied
semen may reveal agglutination (clumping) of sperm. Agglutination may be head-to-
head, head-to-tail, or tail-to-tail and may suggest an inflammatory or immunologic
process. Sperm morphology is subject to great variation and it is unusual to see
specimens that contain more than 80% normal sperm heads.
Morphology is assessed on stained seminal smears and is scored; after viewing at least
100 cells. Typically, you like to see at least 30% of the sperm having normal oval heads,
mid piece and tail. No longer is it felt that increased numbers of tapered, amorphous and
immature cells (stress pattern) are pathonomic of varicoceles, but rather represent altered
testicular function. Semen from normal men coagulates and then over 20-30 plus minutes
liquefies. Delayed liquefaction of semen greater than 60 minutes may indicate disorders
of accessory gland function. Diagnosis of the liquefaction problem should be made if
there is absence of sperm in the post coital test. If sperm are capable of reaching the
cervical mucus, problems of semen liquefaction are not clinically relevant. Increased
semen viscosity, which is unrelated to the coagulation-liquefaction phenomenon,
signifies a disorder of accessory gland function and may effect the accuracy of
assessment of both sperm density and motility. It is only clinically relevant when there
are very few sperm in the post coital test.
The presence of white blood cells in semen should be noted. It is difficult to differentiate
between white blood cells and immature spermatozoa on routine analysis, because both
may appear as round cells in the semen. Peroxidase stain and, more recently monoclonal
antibodies have been utilized to aid in this differentiation. Excessive white cells ( > 1
million/cc) may indicate an infection that may contribute to subfertility. If no
spermatozoa are observed, a qualitative test for fructose should be performed. A low
ejaculate volume and lack of fructose, along with failure of the semen to coagulate,
suggest congenital absence of the vas deferens and seminal vesicles or obstruction of the
ejaculatory ducts. Fructose is androgen-dependent and is produced in the seminal
vesicles.
HORMONE EVALUATION
Most cases of male infertility are non-endocrine in origin. Routine evaluation of
hormonal parameters is not warranted unless sperm density is extremely low or there is
clinical suspicion of an endocrinopathy. The incidence of primary endocrine defects in
infertile men is less than 3%. Such defects are rare in men with a sperm concentration of
greater than 5 million per cc. When an endocrinopathy is discovered, however, specific
hormonal therapy is often successful. Because of the episodic nature of LH secretion and
its short half life, a single LH determination has an accuracy of plus or minus 50%.
Similarly, testosterone is secreted episodically in response to LH pulses and has a diurnal
pattern with an early morning peak. Serum FSH has a longer half life, and these
fluctuations are less obvious. Therefore, I usually just check an FSH and testosterone
level. A low testosterone level is one of the best indicators of hypogonadism of
hypothalamic or pituitary origin. Low LH and FSH values concurrent with low
testosterone levels indicate hypogonadotropic hypogonadism. Elevated FSH and LH
values help to distinguish primary testicular failure (hypergonadotropic hypogonadism)
from secondary testicular failure (hypogonadotropic hypogonadism). Most patients with
primary hypogonadism have severe, irreversible testicular defects. On the other hand,
secondary hypogonadism has a hypothalamic or pituitary origin and infertility may be
correctable. Elevated FSH levels are usually a reliable indicator of germinal epithelial
damage and are usually associated with azoospermia or severe oligospermia, depicting
significant and usually irreversible germ cell damage. In azoospermic and severely
oligospermic patients with normal FSH levels, primary spermatogenic defects cannot be
distinguished from obstructive lesions by hormonal investigation alone. Therefore,
scrotal exploration and testicular biopsy should be considered. An elevated FSH level
associated with small, atrophic testes implies irreversible infertility and a biopsy is not
warranted.
The diagnostic value of prolactin measurement is extremely low in men with semen
abnormalities unless these are associated with decreased libido, erectile dysfunction, and
evidence of hypogonadism. Prolactin measurement is warranted in patients with low
serum testosterone levels without an associated increase in serum LH levels.
CHROMOSOMAL STUDIES
Only in isolated cases has infertility been documented in association with a specific
chromosomal abnormality. Subtle genetic studies can be considered in men with severe
oligospermia and azoospermia to look for both autosomal and sex chromosomal
abnormalities. The diagnostic yield is greatest in men with small testes, azoospermia, and
elevated FSH levels.
IMMUNOLOGIC STUDIES
Couples with repeated abnormal post coital tests. Antisperm antibodies appear to
interfere with normal penetration and transit of sperm through normal cervical mucus.
For as SPA with zona free hamster eggs can demonstrate completion of the human sperm
acrosome reaction and sperm oocyte plasma membrane fusion, only tests with human
zona pellucida can assess the capability of human sperm to bind to the human oocyte.
The hemizona assay uses zona pellucida from non-living human oocytes that have been
microsurgically bisected. Sperm are allowed to interact and bind with the hemizona. The
patient's sperm and fertile sperm are compared utilizing the identical halves of hemizona.
The results are expressed as the hemizona index, i.e. bound sperm by the subfertile man
divided by bound sperm from the fertile donor multiplied by 100. This assay requires
significant expertise in micromanipulation. The hemizona assay is not indicated in the
routine evaluation of the subfertile man.
AcrosomeEvaluation
The acrosome reaction is necessary for fertilization to take place. Evaluating the ability of
sperm to undergo the acrosome reaction may provide an additional assessment of sperm
function. It is possible to determine the acrosomal status of sperm by utilizing electron
microscopy, staining, immunofluorescent techniques and monoclonal antibodies. It is
also possible to induce an acrosome reaction with ionophores and human zona pellucida.
These techniques are labor-intensive and the ability of the acrosomal status to predict
fertility must be confirmed.
Hypo-osmoticSwelling
It has been found that when sperm from normal fertile men are exposed to a known
solution of fructose and sodium citrate, 33-80% of the spermatozoa will exhibit tail
swelling. Sperm that are not viable or sperm with non-functioning membranes do not
swell. This appears to be explained by the ability of the normal cell membrane to
maintain an osmotic gradient. Attempts have been made to correlate this finding with the
fertilization potential for semen samples. Samples with greater than 62% swelling are
able to fertilize ova, whereas less than 60% swelling is observed in samples of infertile
semen. This test has not been widely embraced and is currently a research tool.
Pituitary disease
Pituitary insufficiency (tumors, infiltrative processes, operation, radiation)
Hyperprolactinemia
Hemochromatosis
Exogenous hormones (estrogen-androgen excess, glucocorticoid excess, hyper and
hypothyroidism).
HYPOTHALAMIC DISEASE
Kallmann's syndrome which is an isolated gonadotropin (LH and FSH) deficiency
occurs in both a sporadic and familial form and although uncommon i.e. 1 in 10,000 men,
it is second to Klinefelter's syndrome as a cause of hypogonadism. The syndrome is often
associated with anosmia, congenital deafness, hair lip, cleft palate, craniofacial
asymmetry, renal abnormalities, color blindness. The hypothalamic hormone GnRH
appears to be absent. If exogenous GnRH is administered, both LH and FSH are released
from the pituitary. Except for the gonadotropin deficiency, anterior pituitary function is
intact. The syndrome appears to be inherited either as an autosomal recessive trait or an
autosomal dominant trait with incomplete penetrance. The differential diagnosis should
include delayed puberty. Kallmann's syndrome distinguishing features though are testes
less than 2 cm in diameter and positive family history with the presence of anosmia.
"Fertile eunuch" are individuals with isolated LH deficiency. They have eunuchoid
proportions with variable degrees of virilization and gynecomastia. They
characteristically have large testes and semen containing a few sperm. Plasma FSH levels
are normal but both the serum LH and testosterone concentrations are low normal. The
cause appears to be a partial gonadotropin deficiency in which there is adequate LH to
stimulate testosterone production with resultant spermatogenesis but insufficient
testosterone to promote virilization. In isolated FSH deficiency which is rare, patient's
are normally virilized and have normal testicular size and baseline levels of LH and
testosterone. Sperm counts range from O to a few sperm. Serum FSH levels are low and
do not respond to GnRH stimulation. Congenital hypogonadotropic syndromes are
associated with secondary hypogonadism and a multitude of other somatic findings.
Prader-Willi syndrome is characterized by hypogonadism, hypomentia, hypotonia at birth
and obesity. Laurence-Moon-Bardet-Biedel syndrome is an autosomal recessive trait
characterized by mental retardation, retinitis pigmentosa, polydactyly and hypogonadism.
These syndromes are felt to be due to a defect in hypothalamic deficiency of GnRH.
PITUITARY DISEASE
Pituitary insufficiency may result from tumors, infarctions, iatrogenic causes like
surgery and radiation or one of several infiltrative processes. If pituitary insufficiency
occurs prior to puberty, growth retardation associated with adrenal and thyroid deficiency
is the major clinical presentation. Hypogonadism that occurs in a sexually mature male
usually has its origin in a pituitary tumor. Decreasing libido, impotence and infertility
may occur years before symptoms of an expanding tumor i.e. such as headaches, visual
abnormalities, or thyroid/adrenal hormone deficiency. Once an individual has passed
through normal puberty, it takes a long time for secondary sexual characteristics to
disappear unless adrenal insufficiency is present. The testes will eventually become small
and soft. The diagnosis is made by low serum testosterone levels with low or low normal
plasma gonadotropins concentrations. Depending on the degree of panhypopituitarism,
plasma corticosteroids will be reduced with plasma TSH and growth hormone levels.
With regard to the role of exogenous hormones, adrenocortical tumors, Sertoli cell
tumors, interstitial cell tumors of the testes may all at times be estrogen-producing.
Hepatic cirrhosis is associated with increased endogenous estrogens. Estrogens act
primarily by suppressing pituitary gonadotropin secretion, resulting in secondary
testicular failure. Androgens can also suppress pituitary gonadotropin secretion thereby
leading to secondary testicular failure. The current use of anabolic steroids by certain
athletes may result in temporary sterility. Endogenous androgen excess may be due to an
androgen-producing adrenocortical tumor or testicular tumor but more likely to
congenital adrenal hyperplasia. As a consequence of this disease, the production of
androgenic steroids by the adrenal cortex is increased, resulting in premature
development of secondary sexual characteristics and abnormal phallic enlargement. The
testes failed to mature because of gonadotropin inhibition and are characteristically small.
In the absence of precocious puberty, the diagnosis is extremely difficult since excessive
virilization is difficult to detect in an otherwise normally sexually mature man. Careful
laboratory evaluation is essential. Infertility caused by documented congenital adrenal
hyperplasia is treatable with corticosteroids. Physicians have used corticosteroids in
individuals with idiopathic infertility, but unless these abnormalities can be documented,
steroid therapy has no place.
Noonan's Syndrome is the male counterpart of Turner's Syndrome (X0), and these
individuals typically have similar features i.e. short stature, web neck, low-head ears,
cubitus valgus, ocular abnormalities and cardiovascular abnormalities. Most males with
Noonan's Syndrome have cryptorchidism and diminished spermatogenesis and are
infertile. Those with diminished testicular function will have elevated serum FSH and LH
levels. They demonstrate on chromosomal analysis a sex chromosome abnormality such
as X0/XY mosaicism. There is no treatment for their infertility.
Patients with myotonic dystrophy suffer from delayed muscle relaxation after initial
contraction. The major clinical features also include lenticular opacities, frontal baldness
and testicular atrophy. Inheritance is autosomal dominant and the expression is variable
though 80% will develop testicular atrophy. Pubertal development is usually normal and
testicular damage occurs later in adult life. Leydig cell function remains normal and there
is no gynecomastia.
Bilateral anorchia or vanishing testes syndrome is an extremely rare disorder effecting
about 1 in 20,000 males. Patients will present at birth with non-palpable testes and sexual
immaturity later in life because of the absence of testicular androgens. The karyotype is
normal, but LH and FSH levels are elevated and testosterone is extremely low. In utero
the testes may have been lost due to torsion, trauma, vascular injury or infection.
However, functioning testicular tissue must have been present at least for the first
trimester of fetal life in order for the male reproductive ducts and for the external
genitalia to differentiate along male lines. Testosterone does not increase in response to
HCG stimulation. These patients have eunuchoid proportions but no gynecomastia.
Therapy can only be directed at the testosterone deficiency.
Sertoli-cell-only syndrome or germinal cell aphasia may have several causes including
congenital absence of the germ cells, genetic defects, or androgen resistance. Upon
testicular biopsy there will be complete absence of germinal elements. Clinical findings
include azoospermia in association with normal virilization, testes of normal consistency
but slightly smaller in size, and no gynecomastia. Testosterone and LH levels are normal
but FSH levels are usually elevated. Sometimes in patients who have had other testicular
disorders like mumps, cryptorchidism or radiation/toxin damage, the seminiferous
tubules may also contain only Sertoli cells, but in these men the testes are small and the
histologic pattern is not as uniform. These patients are more likely to have severe
sclerosis and hyalinization as prominent features as well. There is no treatment for their
infertility.
Gonadotoxins like drugs and radiation can effect the germinal epithelium because it is a
rapidly dividing tissue and susceptible to interference of cell division. Cancer
chemotherapy has a dose-dependent effect on testicular germinal epithelium. The
germinal epithelium appears to be more resistant to toxic drugs before puberty than in
adulthood. The alkylating agents like chiromancies, cyclophosphamide and nitrogen
mustard are particular toxic to the testes. In some patients, cryopreservation of semen can
be performed before cancer chemotherapy is begun. Cyproterone, ketoconazole,
spirolactone and alcohol all interfere with testosterone synthesis. Cimetidine is a
testosterone antagonist, blocking peripheral testosterone action. These men will often
present with gynecomastia and have decreased sperm counts.
Recreational drugs like marijuana, heroin, and methadone are associated with lower
serum testosterone levels without a concomitant elevation in LH levels. This suggests a
central abnormality as well as a testicular defect. Certain pesticides like
dibromochloropropane have been found to impair testicular function in men. Germ cells
are particularly sensitive to radiation while the Leydig cells are relatively resistant. At
exposures below 600 rads, germ cell damage is reversible. Above this level of exposure
though permanent damage is likely. Recovered spermatogenesis may take up to 2-3 years
even in men who receive low doses of radiation. Elevated FSH levels reflect the impaired
spermatogenesis, with return to normal once the testes recover.
About 15-25% of adult men who contract mumps can develop orchitis which is more
commonly unilateral though bilateral involvement occurs in about 10% of affected men.
Testicular atrophy can develop within 1 to 6 months or may take years. Fewer than one-
third of men with bilateral orchitis recover normal semen parameters.
The exposed position of the testicles make them susceptible to trauma and subsequent
atrophy. Iatrogenic injury may occur during inguinal surgery and interfere with testicular
blood supply or damage the vas deferens.
Systemic diseases like renal failure resulting in uremia in males is associated with
decreased libido, impotence and altered spermatogenesis and gynecomastia. LH and FSH
levels are elevated and testosterone levels are decreased. The cause of hypogonadism in
uremia is probably multifactorial. It has been found that serum prolactin levels are
elevated in one-fourth of the patients. An excess in estrogen may be contributory. Anti-
hypertensive drugs and uremic neuropathy may also play a role in uremic impotence and
hypogonadism. After successful renal transplantation, uremic hypogonadism improves. A
large percentage of males with cirrhosis of the liver have testicular atrophy, impotence
and gynecomastia. Testosterone levels are decreased. Estradiol is increased as a result of
decreased hepatic extraction of androgens with increased conversion to estrogen
peripherally. LH and FSH levels are only moderately elevated relative to the low serum
testosterone levels. Ethanol also acutely reduces testosterone levels by inhibiting
testicular testosterone synthesis. Many men with sickle cell disease have evidence of
hypogonadism. Even though LH and FSH levels may be variable, testosterone levels are
low. Hypogonadism of sickle cell disease is likely secondary to a mixture of testicular
and pituitary-hypothalamic causes.
Rare heredity disorders due to enzymatic defects can result in defective testosterone
synthesis and are associated with an adequate virilization that is evident at birth as
ambiguous genitalia. Several forms of androgen resistance result in under
masculinization and infertility in males with otherwise normally developed external
genitalia. Diagnosis is made by the finding of abnormal androgen receptors in a culture of
genital skin fiberblasts. Characteristically, there is an elevation testosterone and LH
levels. Proof of this is costly and there is no treatment for their infertility.
A scrotal varicocele is the most common causative finding in infertile men. It results
from backflow of blood secondary to incompetent or absent valves in the spermatic veins.
This valvular deficiency combined with the long vertical course of the internal spermatic
vein on the left side, leads to the formation of most varicoceles on the left side (90%).
Varicoceles are not as commonly seen on the right side because of the oblique course of
the right internal spermatic vein from the vena cava. A unilateral right-sided varicocele
suggests venous thrombosis/tumor or situs inversus. Newer diagnostic tests have shown
the incidence of bilateral varicoceles to be greater than 40%. The incidence of varicoceles
in the adult male population is approximately 20% and in the infertile population
approximately 40%. 50% of men with varicoceles will have impaired semen quality, but
many men varicoceles are fertile. To explain the abnormalities in spermatogenesis with
varicocele, the following theories have been proposed:
Recent experimental evidence has demonstrated bilateral increase in both testicular blood
flow and temperature with altered spermatogenesis. Unfortunately, at least 25-40% of
infertile men have idiopathic infertility for which no cause can be identified. More
known causes will be discovered hopefully as knowledge of male reproductive
physiology expands.
Functional obstruction of sperm transport results from neuropathic insults like injuries
to the sympathetic nerves during retroperitoneal lymph node dissection or pelvic surgery.
This may cause lack of peristalsis of the vas deferens with resultant lack of emission
and/or failure of the bladder neck to close at the time of ejaculation leading to retrograde
ejaculation. Diabetic males with autonomic neuropathy frequently present with both
erectile dysfunction and/or retrograde ejaculation. Spinal cord injury can result in
paraplegia or quadriplegic with resultant erectile dysfunction and lack of emission and
ejaculation. There are many medications such as tranquilizers, antidepressants, and
antihypertensives that may interfere with the sympathetic nervous system as well.
Infections. High concentrations of gram-negative bacteria like E-coli in the semen can
impair sperm motility. Sexually transmitted organisms such as chlamydia trichomatous,
mycoplasma hominis and ureaplasma urealyticulum have rarely been implicated in
reproductive failure. In both animals and humans, there is no convincing evidence to
support the use of routine cultures or empiric therapy in asymptomatic infertile males.
Sexual dysfunction has been reported in up to 20% of infertile males. Decreased sexual
drive, erectile dysfunction, premature ejaculation and failure of intromission are all
potentially correctable causes of reproductive failure. Decreasing libido and erectile
dysfunction may reflect low serum testosterone levels with an organic cause.
Performance anxiety is also often reported and often abated with reassurance.
DIAGNOSTIC TESTING
Semen Analysis
Although semen analysis is not a test of fertility, a carefully performed semen analysis is
a highly predictive indicator of the functional status of the male reproductive hormonal
cycle, spermatogenesis and the patency of the reproductive tract. The initiation of a
pregnancy is the only true measure of fertility and is a couple-related phenomenon. One
must keep in mind that normal values have been difficult to determine for fertile men in
their reproductive years. Clinical studies of infertile patients have established "limits of
adequacy" below which the chance of initiating a pregnancy becomes more difficult.
These parameters are not absolute because some fertile men may have values below these
"limits of adequacy". Conversely, infertile men may have normal semen parameters by
standard analysis techniques because standard evaluation does not assess the functional
integrity of the sperm. The World Health Organization Laboratory Manual for
Examination of Human Semen and Semen-Cervical Mucous Interactions is highly
recommended for technical details.
Most specialists collect at least three specimens in which the seminal parameters are
within 20% of each other before establishing a baseline for semen quality. The semen
specimen is best obtained by masturbation after a two to three day period of abstinence.
The specimen should be assessed within 1-2 hours of collection. Samples obtained by
coitus interruptus or from silastic condoms devoid of spermatocidal agents are less
desirable but satisfactory. Therefore, collection at the site of analysis is ideal. Besides
laboratory error, there are variations in sperm density, motility and morphology among
multiple samples from a given man. Abstinence intervals give s large source of
variability. With each day of abstinence (up to one week) semen volume increases by 0.4
cc, sperm concentration by 10-15 million per cc, and total sperm count by 50-90 million.
Sperm motility and morphology appear to be unaffected by 5-7 days of abstinence, but
longer periods lead to impaired motility. Interpretation of semen analysis must take into
consideration the variations between samples that exist in individuals. The minimum
number of specimens to define good or poor quality of semen is three samples over a 6-8
week interval with a consistent period of abstinence of 2-3 days. In a longitudinal
analysis of semen from both fertile and infertile men, it was found that 97% of men with
initial good sperm concentration would continue to show good density after as many as 3-
6 specimens. Those rated poor at first also remained poor in future visits. For those rated
equivocal, first visit was of little value and at least three visits were needed to obtain
stability.
Semen volume must be taken into consideration assessing total sperm production by the
testes. Semen volume per se, however, effects fertility only when it falls below 1.5 cc due
to the inadequate buffering of vaginal acidity or when the volume is greater than 5 cc.
Low volumes may be associated with incomplete collection, retrograde ejaculation,
ejaculatory duct obstruction, or androgen deficiency. For most clinicians, a sperm
concentration of less than 20 million per cc is the lower limit of normal. Sperm motility is
the single most important measure of semen quality and can be a compensatory factor in
men with low sperm counts.
Sperm motility is usually rated in two ways: the number of motile sperm as a percentage
of the total, and the quality of forward progressive sperm movement i.e., how fast and
how straight the sperm swims. The degree of forward progression is a classification based
on the pattern displayed by the majority of motile sperm. It ranges from zero (no
movement) to 4 (excellent forward progression). Typically, you want to see at least 50%
of the sperm with good forward progression. Microscopic evaluation of the liquefied
semen may reveal agglutination (clumping) of sperm. Agglutination may be head-to-
head, head-to-tail, or tail-to-tail and may suggest an inflammatory or immunologic
process. Sperm morphology is subject to great variation and it is unusual to see
specimens that contain more than 80% normal sperm heads.
Morphology is assessed on stained seminal smears and is scored; after viewing at least
100 cells. Typically, you like to see at least 30% of the sperm having normal oval heads,
mid piece and tail. No longer is it felt that increased numbers of tapered, amorphous and
immature cells (stress pattern) are pathonomic of varicoceles, but rather represent altered
testicular function. Semen from normal men coagulates and then over 20-30 plus minutes
liquefies. Delayed liquefaction of semen greater than 60 minutes may indicate disorders
of accessory gland function. Diagnosis of the liquefaction problem should be made if
there is absence of sperm in the post coital test. If sperm are capable of reaching the
cervical mucus, problems of semen liquefaction are not clinically relevant. Increased
semen viscosity, which is unrelated to the coagulation-liquefaction phenomenon,
signifies a disorder of accessory gland function and may effect the accuracy of
assessment of both sperm density and motility. It is only clinically relevant when there
are very few sperm in the post coital test.
The presence of white blood cells in semen should be noted. It is difficult to differentiate
between white blood cells and immature spermatozoa on routine analysis, because both
may appear as round cells in the semen. Peroxidase stain and, more recently monoclonal
antibodies have been utilized to aid in this differentiation. Excessive white cells ( > 1
million/cc) may indicate an infection that may contribute to subfertility. If no
spermatozoa are observed, a qualitative test for fructose should be performed. A low
ejaculate volume and lack of fructose, along with failure of the semen to coagulate,
suggest congenital absence of the vas deferens and seminal vesicles or obstruction of the
ejaculatory ducts. Fructose is androgen-dependent and is produced in the seminal
vesicles.
HORMONE EVALUATION
Most cases of male infertility are non-endocrine in origin. Routine evaluation of
hormonal parameters is not warranted unless sperm density is extremely low or there is
clinical suspicion of an endocrinopathy. The incidence of primary endocrine defects in
infertile men is less than 3%. Such defects are rare in men with a sperm concentration of
greater than 5 million per cc. When an endocrinopathy is discovered, however, specific
hormonal therapy is often successful. Because of the episodic nature of LH secretion and
its short half life, a single LH determination has an accuracy of plus or minus 50%.
Similarly, testosterone is secreted episodically in response to LH pulses and has a diurnal
pattern with an early morning peak. Serum FSH has a longer half life, and these
fluctuations are less obvious. Therefore, I usually just check an FSH and testosterone
level. A low testosterone level is one of the best indicators of hypogonadism of
hypothalamic or pituitary origin. Low LH and FSH values concurrent with low
testosterone levels indicate hypogonadotropic hypogonadism. Elevated FSH and LH
values help to distinguish primary testicular failure (hypergonadotropic hypogonadism)
from secondary testicular failure (hypogonadotropic hypogonadism). Most patients with
primary hypogonadism have severe, irreversible testicular defects. On the other hand,
secondary hypogonadism has a hypothalamic or pituitary origin and infertility may be
correctable. Elevated FSH levels are usually a reliable indicator of germinal epithelial
damage and are usually associated with azoospermia or severe oligospermia, depicting
significant and usually irreversible germ cell damage. In azoospermic and severely
oligospermic patients with normal FSH levels, primary spermatogenic defects cannot be
distinguished from obstructive lesions by hormonal investigation alone. Therefore,
scrotal exploration and testicular biopsy should be considered. An elevated FSH level
associated with small, atrophic testes implies irreversible infertility and a biopsy is not
warranted.
The diagnostic value of prolactin measurement is extremely low in men with semen
abnormalities unless these are associated with decreased libido, erectile dysfunction, and
evidence of hypogonadism. Prolactin measurement is warranted in patients with low
serum testosterone levels without an associated increase in serum LH levels.
CHROMOSOMAL STUDIES
Only in isolated cases has infertility been documented in association with a specific
chromosomal abnormality. Subtle genetic studies can be considered in men with severe
oligospermia and azoospermia to look for both autosomal and sex chromosomal
abnormalities. The diagnostic yield is greatest in men with small testes, azoospermia, and
elevated FSH levels.
IMMUNOLOGIC STUDIES
For as SPA with zona free hamster eggs can demonstrate completion of the human sperm
acrosome reaction and sperm oocyte plasma membrane fusion, only tests with human
zona pellucida can assess the capability of human sperm to bind to the human oocyte.
The hemizona assay uses zona pellucida from non-living human oocytes that have been
microsurgically bisected. Sperm are allowed to interact and bind with the hemizona. The
patient's sperm and fertile sperm are compared utilizing the identical halves of hemizona.
The results are expressed as the hemizona index, i.e. bound sperm by the subfertile man
divided by bound sperm from the fertile donor multiplied by 100. This assay requires
significant expertise in micromanipulation. The hemizona assay is not indicated in the
routine evaluation of the subfertile man.
AcrosomeEvaluation
The acrosome reaction is necessary for fertilization to take place. Evaluating the ability of
sperm to undergo the acrosome reaction may provide an additional assessment of sperm
function. It is possible to determine the acrosomal status of sperm by utilizing electron
microscopy, staining, immunofluorescent techniques and monoclonal antibodies. It is
also possible to induce an acrosome reaction with ionophores and human zona pellucida.
These techniques are labor-intensive and the ability of the acrosomal status to predict
fertility must be confirmed.
Hypo-osmoticSwelling
It has been found that when sperm from normal fertile men are exposed to a known
solution of fructose and sodium citrate, 33-80% of the spermatozoa will exhibit tail
swelling. Sperm that are not viable or sperm with non-functioning membranes do not
swell. This appears to be explained by the ability of the normal cell membrane to
maintain an osmotic gradient. Attempts have been made to correlate this finding with the
fertilization potential for semen samples. Samples with greater than 62% swelling are
able to fertilize ova, whereas less than 60% swelling is observed in samples of infertile
semen. This test has not been widely embraced and is currently a research tool.
BACTERIOLOGIC INVESTIGATION
In azoospermic patients or selected cases of severe oligospermia with normal FSH levels,
primary spermatogenic defects cannot be differentiated from obstructive lesions by
hormonal investigation alone, and testicular biopsy and sometimes vasography should be
considered. When patients have azoospermia or severe oligospermia in conjunction with
markedly shrunken testes and serum FSH levels that are at least twice normal, testicular
biopsy can be avoided as it will indicate untreatable testicular pathology and only provide
a definitive diagnosis which allows the patient to investigate alternatives. The exception
is the patient who has undergone chemotherapy in whom the elevated FSH level may
normalize with return of spermatogenesis. Before biopsy, at least two semen analysis
should reveal azoospermia and retrograde ejaculation should be ruled out by examining a
post ejaculatory urine specimen. In men with acidic semen, i.e. pH of less than 7.0 and a
volume of less than 1 cc, suspect ejaculatory duct obstruction or congenital absence of
the seminal vesicles and vas deferens. For confirmation, seminal fructose levels should be
determined. The presence of fructose rules out obstruction or atresia of the ejaculatory
ducts but does not verify total ductal patency. Only when there is clinical suggestions of
different pathologic conditions on each side are bilateral biopsies needed. The testicular
tissue is always placed atraumatically into a container of Bouin's or Zenker's solution.
Formalin should be avoided as it distorts the testicular architecture.
Vasography is used to rule out obstruction of the vas deferens, seminal vesicles, and
ejaculatory ducts. Vasography should be performed only at the time of definitive
reconstructive surgery. A vasotomy is generally performed at the junction of the straight
and convoluted portions of the vas. Any fluid obtained from the vasotomy is evaluated
for the presence of sperm. Patency of the ductal structures distal to this point is assessed
by the injection of radioopaque contrast solution. Injection of 3-5 cc of 50% Hypaque or
Renografin-60 will provide adequate films of the vas, seminal vesicles and ejaculatory
ducts. Methylene blue may also be instilled as the bladder is catheterized. The presence
of blue or green urine documents patency distal to the instillation site. Retrograde
injection of solution towards the testis makes images of the epididymal anatomy that are
extremely difficult to interpret. There is also significant risk of causing epididymal injury
and should be avoided.
RADIOLOGIC INVESTIGATION
Both clinical and laboratory investigations have provided convincing evidence that
varicoceles are detrimental to spermatogenesis in some men. It has been shown that
improvement in semen quality after varicocelectomy bares no relation to the palpable size
of the varicocele. Because small but clinically significant varicoceles may be missed even
on careful physical exam, several diagnostic techniques have been tried. The doppler
pencil-probe stethoscope was one of the earliest techniques and is easily utilized in an
office setting. If the clinician is still uncertain as to the presence of a varicocele, scrotal
ultrasonography is a readily available non-invasive method.
Color flow duplex ultrasonography is a superior way to measure the diameters of the
spermatic cord veins by imaging these vessels, at rest and during a Valsalva maneuver, as
well as to quantify and qualify the flow of blood through these veins. It has been shown
to be 85% sensitive in the detection of subclinical varicoceles when venography was used
as the "gold standard". Duplex ultrasonography is certainly useful when there is a
question on physical examination because it is an objective characterization of the
pampiniform veins. Venography seems to be the most specific method of identification of
varicoceles but it is invasive and associated with some morbidity. It is also expensive and
so should be reserved for use in recurrent varicoceles for postoperative detection of
aberrant veins. Transrectal ultrasonography is ideally suited now for evaluation of the
prostate, seminal vesicles and ejaculatory ducts in patients with azoospermia or low
ejaculate volumes. As discussed previously, the differential diagnoses of azoospermia
included endocrinopathy, testicular failure, and obstruction. Differential diagnosis of low
ejaculatory volume includes hypogonadism, retrograde ejaculation, failure of emission,
seminal vesicle aplasia or hypoplasia and ejaculatory duct obstruction. Although
vasography has been used to visualize the seminal vesicles and ejaculatory ducts,
transrectal ultrasonography is accurate, inexpensive and relatively non-invasive. It can
provide detailed images of the seminal vesicles and ejaculatory ducts.
TREATMENT
Varicocelectomy
The relationship between varicocele, altered spermatogenesis, and infertility is now so
widely accepted that varicocelectomy is the most common surgical procedure for
infertility in males. The term varicocelectomy as it is utilized here is actually a misnomer.
The procedure should be termed internal spermatic vein ligation, as varicocelectomy
implies that the veins are actually being removed and they are instead being ligated. This
operation improves semen quality in about two-thirds of men and basically doubles the
chance of conception. Ligation of varicoceles eliminates testicular venous reflux by
interruption of the internal spermatic veins. The operation is usually performed through a
small inguinal incision though modification of the older Palomo procedure, which is a
retroperitoneal approach, is certainly acceptable. The scrotal approach is mentioned only
for completeness though is not recommended because of the numerous small veins
encountered as well as the possibility of arterial injury is greater. Percutaneous
venographic occlusion is also an alternative to surgery but small veins outside the
spermatic cord that are visualized during an open surgical procedure are not easily
embolizable with the percutaneous approach. Laparoscopic techniques to treat
varicoceles are also currently utilized and at this time have no clear cut advantage over a
small inguinal incision. Complications following varicocelectomy include hydrocele
formation, epididymitis, injury to the internal spermatic artery and persistent or recurrent
scrotal varicoceles. Fortunately, this occurs in less than 3-5% of patients.
Because sperm continues to be manufactured by the testes and attempt to travel through
the epididymis, pressure-induced extravasation may occur at any point within the
epididymal tubule. This results in a local inflammatory reaction that effectively blocks
the movement of sperm. When this situation is recognized at the time of vasectomy
reversal, an epididymovasostomy or vasoepididymostomy is required. This procedure is
more technically demanding. Critical to the success of a vasoepididymal anastomosis is
the ability to visualize the 0.2 to 0.4 mm lumen of the opened epididymal tubule exuding
sperm, and to approximate it accurately to the vasal lumen. Epididymal obstruction can
be the result of 1) congenital anatomical abnormalities of the vas/epididymis; 2)
inflammatory process, and 3) vasal obstruction. It is apparent that the results of
microsurgical reconstruction procedures indicate that sperm which traverse greater
portions of the epididymis are functionally superior. Therefore, the greater the length of
epididymis that the sperm traverse, the better the pregnancy rate. Patency rates have been
reported to be between 50% and 70% with pregnancy rates varying between 15 and 30%.
Transurethral Resection of Ejaculatory Duct
Patients who present with azoospermia and even sometimes oligo-asthenospermia,
normal sized testes, and a normal testicular biopsy in conjunction with transrectal
ultrasound findings of dilated ejaculatory ducts are good candidates for transurethral
resection of the ejaculatory ducts. The orifices of the ejaculatory ducts exit within the
prostatic urethra just lateral to the verumontanum. Under anesthesia they are inspected
endoscopically and then can be incised or unroofed. In select cases, transurethral
resection of the ejaculatory ducts has resulted in marked improvement in semen
parameters, and pregnancies have been achieved.
MEDICAL MEASURES
Endocrine Therapy
Infertile men with hypogonadotropic hypogonadism (secondary hypogonadism) are the
only appropriate candidates for exogenous gonadotropin therapy. For initiation of
spermatogenesis, LH must be given to stimulate the Leydig cells to produce high
intratesticular testosterone levels. hCG (Pregnyl or Profasi) 2,000 IU intramuscularly
three times a week is usually effective in stimulating adequate production of testosterone
for full virilization. Once the patient is fully virilized and 8-12 months of hCG therapy
have not led to the production of sperm, then FSH therapy should be initiated. FSH is
available as human menopausal gonadotropin (hMG). The commercial preparation
Pergonal contains 75 IU of FSH and 75 IU of LH per vial. The usual dosage is 1/2 to 1
vial intramuscularly three times weekly. Since hCG and hMG are compatible in solution,
the same syringe may be used. It takes months for sperm to appear in the ejaculate after
initiation of FSH therapy. With the normal response, most patients achieve a sperm count
of between 2 and 5 million sperm per ejaculate and then impregnation is possible. Once a
pregnancy has occurred, the FSH therapy can be stopped. Spermatogenesis can be
maintained with hCG alone. An alternative to exogenous gonadotropin usage is the use of
GnRH to stimulate LH and FSH endogenously. GnRH must be given in a pulsatile
manner as continuous administration down-regulates the pituitary. The initial dosage is
25-50 ng/kilogram every two hours by a small infusion pump. Both the gonadotropins
and GnRH are expensive. Although GnRH achieves a more physiologic pattern of
gonadotropin stimulation, its superiority has yet to be proved. Pituitary disease is not
amenable to GnRH therapy, and combined treatment with hCG and hMG will be
necessary. Individuals with the fertile eunuch syndrome (partial LH deficiency) may
respond to hCG therapy alone.
As empirical medical treatment of male factor infertility has had limited success, semen
processing and intrauterine insemination have become increasingly used to overcome the
problems of reduced sperm number and motility. Semen processing is simply in-vitro
manipulation of semen to enhance sperm function. It is done in an attempt to remove
adverse seminal fluid factors and to extract a more normal and motile sperm population.
Simple processing methods rely on dilution of the semen and centrifugation followed by
resuspension of the sperm pellet in culture medium such as Ham's F10. More elaborate
methods of sperm processing include swim-up procedures, centrifugation through Percoll
density gradients, etc. On occasion, the patient's sperm may survive poorly in these
procedures and it is desirable to test the semen in advance for the most appropriate
preparative method. The above is followed by intrauterine insemination. Intrauterine
inseminations principle indication was for cervical factor. It is logical that intrauterine
insemination will bypass problems with the cervix or its secretion. The use of intrauterine
insemination for male factor cases, immunological infertility, or unexplained infertility is
widespread at this time, although the success rates are not optimal.