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 sub fertile, 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.
can be divided into pretesticular, testicular, and posttesticular.
Pretesticular Causes of Infertility
causes of infertility include congenital or acquired diseases of the
hypothalamus, pituitary, or peripheral organs that alter the
Disorders of the hypothalamus lead to
hypogonadotropic hypogonadism. If GnRH is not secreted, the
pituitary does not release LH and FSH. Ideally, patients respond to
replacement with exogenous GnRH or HCG, an LH analogue, although
this does not always occur.
A failure of
GnRH secretion without any discernible underlying cause may be
observed alone (isolated) or as part of Kallmann syndrome, which
is associated with midline defects such as anosmia, cleft lip
and cleft palate, deafness, cryptorchidism, and color blindness.
Kallmann syndrome has been described in both familial (X-linked
and autosomal) and sporadic forms, and its incidence is
estimated as 1 case per 10,000-60,000 births.
A failure of
GnRH neurons to migrate to the proper location in the
hypothalamus has been implicated. Patients generally have long
arms and legs due to a delayed closure of the epiphyseal plates,
delayed puberty, and atrophic testis. Testosterone therapy may
allow patients to achieve normal height but does not improve
spermatogenesis. Exogenous testosterone should never be
administered in an attempt to boost sperm production because it
actually decreases intratesticular testosterone levels owing to
feedback inhibition of GnRH release.
and HCG have been used but result in only 20% achieving complete
recombinant human FSH to HCG has been shown to be effective in
achieving spermatogenesis in most patients.
with adult-onset idiopathic hypogonadotropic hypogonadism may
respond to clomiphene citrate therapy.
syndrome: Patients have characteristic obesity, mental
retardation, small hands and feet, and hypogonadotropic
hypogonadism due to a GnRH deficiency. Prader-Willi syndrome is
caused by a disorder of genomic imprinting with deletions of
paternally derived chromosome arm 15q11-13.
syndrome: Patients with this syndrome have retinitis pigmentosa
and polydactyly. Infertility is due to hypogonadotropic
conditions: Various other lesions and diseases, such as CNS
tumors, temporal lobe seizures, and many drugs (eg, dopamine
antagonists) may interrupt the hypothalamic-pituitary axis at
Both pituitary insufficiency and
pituitary excess cause infertility. Pituitary failure may be
congenital or acquired. Acquired causes include tumor, infarction,
radiation, infection, or granulomatous disease. Nonfunctional
pituitary tumors may compress the pituitary stalk or the
gonadotropic cells, interrupting the proper chain of signals leading
to pituitary failure. In contrast, functional pituitary tumors may
lead to unregulated gonadotropin release or prolactin excess,
interrupting the proper signaling.
adenoma is the most common functional pituitary tumor. Prolactin
stimulates breast development and lactation; therefore, patients
with infertility due to a prolactinoma may have gynecomastia and
galactorrhea. In addition, loss of peripheral visual fields
bilaterally may be due to compression of the optic chiasm by the
growing pituitary tumor.
level of more than 150 mcg/L suggests a pituitary adenoma, while
levels greater than 300 mcg/L are nearly diagnostic. Patients
should undergo an MRI or CT scan of the sella turcica for
diagnostic purposes to determine whether a microprolactinoma or
a macroprolactinoma is present.
a dopamine agonist, is used to suppress prolactin levels and is
the therapy of choice for microprolactinomas. Cabergoline is
also a treatment option. Some men respond with an increase in
testosterone levels; many also recover normal sperm counts.
Transsphenoidal resection of a microprolactinoma is 80-90%
successful, but as many as 17% recur. Surgical therapy of a
macroprolactinoma is rarely curative, although this should be
considered in patients with visual-field defects or those who do
not tolerate bromocriptine.
deficiency (fertile eunuch): In these patients, LH levels are
decreased while FSH levels are within the reference range.
Patients have eunuchoidal body habitus, large testis, and a low
ejaculatory volume. The treatment of choice is exogenous HCG.
deficiency: This is a very rare cause of infertility. Patients
present with oligospermia but have LH levels within the
reference range. Treatment is with human menopausal gonadotropin
(HMG) or exogenous FSH.
Patients with thalassemia have ineffective erythropoiesis and
undergo multiple blood transfusions. Excess iron from multiple
transfusions may get deposited in the pituitary gland and the
testis, causing parenchymal damage and both pituitary and
testicular insufficiency. Treatment is with exogenous
gonadotropins and iron-chelating therapy.
disease: Increased cortisol levels cause a negative feedback on
the hypothalamus, decreasing GnRH release.
The hypothalamus-pituitary axis may be
interrupted by hormonally active peripheral tumors or other
exogenous factors, due to cortical excess, cortical deficiency, or
may be produced by adrenal hyperplasia, adenomas, carcinoma, or
lung tumors. High cortisol levels may also be seen with
exogenous steroid use, such as that administered to patients
with ulcerative colitis, asthma, arthritis, or organ transplant.
For example, high cortisol levels are seen in patients with
Cushing syndrome, which causes negative feedback on the
pituitary to decrease LH release.
deficiency may be seen in patients with adrenal failure due to
infection, infarction, or congenital adrenal hyperplasia (CAH).
CAH may be due to the congenital deficiency of one of several
adrenal enzymes, the most common of which is 21-hydroxylase
deficiency. Because cortisol is not secreted, a lack of feedback
inhibition on the pituitary gland occurs, leading to
adrenocorticotropic hormone (ACTH) hypersecretion. This leads to
increased androgen secretion from the adrenal gland, causing
feedback inhibition of GnRH release from the hypothalamus.
Patients present with short stature, precocious puberty, small
testis, and occasional bilateral testicular rests. Screening
tests include increased plasma 17-hydroxylase and urine
may be seen in patients with Sertoli cell tumors, Leydig tumors,
liver failure, or severe obesity. Estrogen causes negative
feedback on the pituitary gland, inhibiting LH and FSH release.
Testicular Causes of Infertility
problems may be chromosomal or non chromosomal in nature. While
chromosomal failure is usually caused by abnormalities of the sex
chromosomes, autosomal disorders are also observed.
An estimated 6-13% of infertile men
have chromosomal abnormalities (compared with 0.6% of the general
population). Patients with azoospermia or severe oligospermia are
more likely to have a chromosomal abnormality (10-15%) than
infertile men with sperm density within the reference range (1%). A
karyotype test and a Y chromosome test for microdeletions are
indicated in patients with nonobstructive azoospermia or severe
oligospermia (<5 million sperm/mL), although indications are
syndrome is the most common chromosomal cause of male
infertility, estimated to be present in 1 per 500-1000 male
births. Classic Klinefelter syndrome has a 47, XXY karyotype and
is caused by a nondisjunction during the first meiotic division,
more commonly of maternal origin; mosaic forms are due to
nondisjunction following fertilization. The only known risk
factor for Klinefelter syndrome is advanced maternal age.
Infertility is caused by primary testicular failure, and most
patients are azoospermic. Hormonal analysis reveals increased
gonadotropin levels, while 60% have decreased testosterone
levels. Surprisingly, most patients have normal libido,
erections, and orgasms, so testosterone therapy has only a
limited role; exogenous testosterone may also suppress any
underlying sperm production.
examination reveals gynecomastia, small testis, and eunuchoid
body habitus due to delayed puberty. In some patients, secondary
sex characteristics develop normally, but they are usually
completed late. These men are at a higher risk for breast
cancer, leukemia, diabetes, empty sella syndrome, and pituitary
tumors. Testicular histology reveals hyalinization of
seminiferous tubules. Some men with Klinefelter syndrome may be
able to conceive with the help of assisted reproductive
techniques. Of azoospermic patients with Klinefelter syndrome,
20% show the presence of residual foci of spermatogenesis.
Although the XXY pattern is observed in the spermatogonia and
primary spermatocytes, many of the secondary spermatocytes and
spermatids have normal patterns. The chromosomal pattern of the
resultant embryos can be assessed with preimplantation genetic
XX male (sex
reversal syndrome): An XX karyotype is due to a crossover of the
sex-determining region (SRY) of the Y chromosome (with the
testis determining factor) to either the X chromosome or an
autosome. Patients are often short, with small firm testis and
gynecomastia, but they have a normal-sized penis. Seminiferous
tubules show sclerosis.
XYY male: An
XYY karyotype is observed in 0.1-0.4% of newborn males. These
patients are often tall and severely oligospermic or azoospermic.
This pattern has been linked with aggressive behavior. Biopsy
reveals maturation arrest or germ cell aplasia. Functional sperm
that are present may have a normal karyotype.
(46, XY): Patients with Noonan syndrome, also known as male
Turner syndrome, have physical characteristics similar to that
of women with Turner syndrome (45, X). Features include a webbed
neck, short stature, low-set ears, ptosis, shield-like chest,
lymphedema of hands and feet, cardiovascular abnormalities, and
cubitus valgus. Leydig cell function is impaired, and most
patients are infertile due to primary testicular failure.
dysgenesis (45, X/46, XY): Patients have ambiguous genitalia, a
testis on one side, and a streaked gonad on the other.
microdeletion syndrome: The long arm of the Y chromosome (Yq) is
considered critical for fertility, especially Yq11.23 (interval
6). Macroscopic deletions of Yq11 are often observed in patients
with azoospermia, although many new microdeletions have been
implicated as a significant cause of infertility. These
microdeletions are not observed on regular karyotype; rather,
their identification requires polymerase chain reaction (PCR)–based
sequence-tagged site mapping or Southern blot analysis. Three
regions have been described, called azoospermic factors a, b,
and c (AZFa, AZFb, AZFc). These deletions are observed in 3-19%
of patients with idiopathic infertility and 6-14% of patients
with oligospermia, although up to 7% of patients with other
known causes of infertility may also be found to have a
deletion. Patients with azoospermia or severe oligospermia
seeking assisted reproductive techniques should be screened.
anorchia (vanishing testis syndrome): Patients have a normal
male karyotype (46, XY) but are born without testis bilaterally.
The male phenotype proves that androgen was present in utero.
Potential causes are unknown, but it may be related to
infection, vascular disease, or bilateral testicular torsion.
Karyotype shows a normal SRY gene. Patients may achieve normal
virilization and adult phenotype by the administration of
exogenous testosterone, but they are infertile.
These patients have mild testicular dysfunction with varying
degrees of reduction in germ cell number. LH and FSH levels are
dystrophy: This is an autosomal dominant defect in the
dystrophin gene that causes a delay in muscle relaxation after
contraction. Seventy-five percent of patients have testicular
atrophy and primary testicular failure due to degeneration of
the seminiferous tubules. Leydig cells are normal. Histology
reveals severe tubular sclerosis. No effective therapy exists.
Nonchromosomal Testicular Failure
that is nonchromosomal in origin may be idiopathic or acquired by
gonadotoxic drugs, radiation, orchitis, trauma, or torsion.
A varicocele is
a dilation of the veins of the pampiniform plexus of the
scrotum. Although varicoceles are present in 15% of the male
population, a varicocele is considered the most common
correctable cause of infertility (30-35%) and the most common
cause of secondary (acquired) infertility (75-85%). Varicoceles
are observed more commonly on the left side than the right.
Those with isolated right-sided varicoceles should be evaluated
for retroperitoneal pathology.
generally asymptomatic, and most men with varicoceles do not
have infertility or testicular atrophy. However, varicoceles may
lead to impaired testicular spermatogenesis and steroidogenesis,
potentially due to an increased intratesticular temperature,
reflux of toxic metabolites, and/or germ cell hypoxia as
potential causes of these changes, and this appears to be
progressive over time.
lead to an increased incidence of sperm immaturity, apoptosis,
and necrosis with severe disturbances in meiotic segregation
compared to fertile men without varicoceles, and these
parameters generally improve after repair.
Patients with a
grade 2-3 varicocele (visible or palpable) associated with
infertility should have the varicocele repaired. After repair,
40-70% of patients have improved semen parameters, while 40% are
able to achieve a pregnancy without other interventions. Those
with a varicocele diagnosable only on scrotal ultrasonography
will likely not benefit from repair. Adolescents with a
varicocele and testicular atrophy or lack of growth should
similarly undergo repair. Controversy exists regarding whether
to routinely repair an adolescent varicocele not associated with
In those with
azoospermia and a varicocele, sperm may appear after repair in
up to one third, but most of these men return to an azoospermic
state within a few months. If sperm appears, these men should be
An estimated 3%
of full-term males are born with an undescended testicle, but
fewer than 1% remain undescended by age 1 year. Undescended
testicle may be isolated or may be observed as part of a
syndrome such as prune belly syndrome. Patients are at increased
risk of infertility, even if the testicle is brought down into
the scrotum, as the testicle itself may be inherently abnormal.
The farther from the scrotum, and the longer duration that the
testicle resides outside the scrotum, the greater the likelihood
of infertility. Testicular histology typically reveals a
decreased number of Leydig cells and decreased spermatogenesis.
Cryptorchidism may be due to inherent defects in both testes
because even men with unilateral cryptorchidism have lower than
expected sperm counts.
Testicular trauma is the second most common acquired cause of
infertility. The testes are at risk for both thermal and
physical trauma because of their exposed position.
cells-only syndrome (germinal cell aplasia): Patients with
germinal cell aplasia have LH and testosterone levels within the
reference range but have an increased FSH level. The etiology is
unknown but is probably multifactorial. Patients have with
small- to normal-sized testes and azoospermia, but normal
secondary sex characteristics. Histology reveals seminiferous
tubules lined by Sertoli cells and a normal interstitium,
although no germ cells are present.
Chemotherapy is toxic to actively dividing cells. In the
testicle, germ cells (especially up to the preleptotene stage)
are especially at risk. The agents most often associated with
infertility are the alkylating agents such as cyclophosphamide.
For example, treatment for Hodgkin disease has been estimated to
lead to infertility in as many as 80-100% of patients.
therapy: While Leydig cells are relatively radioresistant
because of their low rate of cell division, the Sertoli and germ
cells are extremely radiosensitive. If stem cells remain viable
after radiation therapy, patients may regain fertility within
several years. However, some have suggested that patients should
avoid conception for 6 months to 2 years after completion of
radiation therapy because of the possibility of chromosomal
aberrations in their sperm caused by the mutagenic properties of
radiation therapy. Even with the testis shielded, radiation
therapy below the diaphragm may lead to infertility due to the
release of reactive oxygen free radicals.
The most common
cause of acquired testicular failure in adults is viral orchitis,
such as that caused by the mumps virus, echovirus, or group B
arbovirus. Of adults with who are infected with mumps, 25%
develop orchitis; two thirds of cases are unilateral, and one
third are bilateral. While orchitis develops a few days after
the onset of parotid gland inflammation, it may also precede it.
The virus may either directly damage the seminiferous tubules or
indirectly cause ischemic damage as the intense swelling leads
to compression against the tough tunica albuginea. After
recovery, the testicle may return to normal or may atrophy.
Atrophy is observed within 1-6 months, and the degree of atrophy
does not correlate with the severity of orchitis or infertility.
Normal fertility is observed in three fourths of patients with
unilateral mumps orchitis and in one third of patients in
disease: Leprosy and sarcoidosis may infiltrate the testicle and
lead to testicular failure.
disease: Sickling of cells within the testis leads to
microinfarcts and secondary testicular failure.
of alcohol, cigarettes, caffeine, and marijuana may lead to
causes: Despite a thorough workup, nearly 25% of men have no
discernible cause for their infertility.
Causes of Infertility
causes of infertility include problems with sperm transportation
through the ductal system, either congenital or acquired. Genital
duct obstruction is a potentially curable cause of infertility and
is observed in 7% of infertile patients. Additionally, the sperm may
be unable to cross the cervical mucus or may have ultrastructural
of the ductal system: An increased rate of duct obstruction is
observed in children of mothers who were exposed to DES during
pregnancy. Segmental dysplasia is defined as a vas deferens with at
least 2 distinct sites of vasal obstruction.
fibrosis: CF is the most common genetic disorder in whites.
Patients with CF nearly uniformly have CBAVD. The cystic
fibrosis transmembrane regulator (CFTR) protein plays a role in
mesonephric duct development during early fetal life, so these
patients may also have urinary tract abnormalities. Patients may
be candidates for assisted reproduction techniques after
appropriate genetic screening in the partner.
blockage of the ductal system: Genital ducts may become
obstructed secondary to infections, such as chlamydia,
gonorrhea, tuberculosis, and smallpox. Young syndrome is a
condition that leads to inspissation of material and subsequent
blockage of the epididymis. Trauma, previous attempts at sperm
aspiration, and inguinal surgery may also result in ductal
blockage. Small calculi may block the ejaculatory ducts, or
prostatic cysts may extrinsically block the ducts. Scrotal
surgery, including vasectomy, hydrocelectomy (5-6%), and
spermatocelectomy (up to 17%), may lead to epididymal injury and
antibodies: Antisperm antibodies bind to sperm, impair motility,
and lead to clumping, impairing movement through the female
reproductive tract and interaction with the oocyte.
syndrome may be isolated or part of Kartagener syndrome with
situs inversus. Because of a defect in the dynein arms, spokes,
or microtubule doublet, cilia in the respiratory tract and in
sperm do not function properly. In addition to sperm immobility,
patients experience sinusitis, bronchiectasis, and respiratory
duct obstruction: Complete and partial ejaculatory duct
obstruction has been implicated as a cause of 1-5% of patients
with male infertility. Patients may have a normal palpable vas
deferens bilaterally but show decreased ejaculate volume and
hemospermia and may experience pain upon ejaculation. Etiologies
include cysts (midline and eccentric), ductal calcification and
stones, postinfectious, and postoperative. Transrectal
ultrasonography (TRUS) may reveal enlarged seminal vesicles, but
this is not universal. Seminal vesicle aspiration revealing
numerous sperm or a dynamic test such as injection of indigo
carmine into the seminal vesicle or ejaculatory duct may be
necessary for diagnosis.
ejaculation may be due to an open bladder neck or a lack of
rhythmic contractions during ejaculation. Etiologies include
diabetic neuropathy, bladder neck surgery, RPLND, transurethral
prostatectomy, colon or rectal surgery, multiple sclerosis,
spinal cord injury, or the use of medicines such as
alpha-antagonists. Diagnosis is suggested by history, a low
ejaculate volume, and the observance of 10-15 sperm per
high-power field (HPF) in the postejaculatory urine.
Symptoms of Male Infertility
For men, the most typical symptom of male infertility that may
signal an underlying fertility problem is six months of unprotected
intercourse without successful conception. Unlike many cases of
female infertility, most men do not show any physical symptoms of
infertility problems, but continue to have trouble getting pregnant
with their partner. Nonetheless, there are some infertility symptoms
that may be experienced along with difficulty getting pregnant as a
result of a specific, underlying cause of infertility.
number of risk factors are linked to male infertility. They include:
Age. Men older than 35 may have a
gradual decline in fertility.
Tobacco smoking. Fertility may
improve when you quit smoking.
Alcohol use. Heavy alcohol use can
lower testosterone levels, cause erectile dysfunction and
decrease sperm production.
Being overweight — or too thin.
Being at an unhealthy weight can reduce sperm count.
Celiac disease. A digestive
disorder caused by a sensitivity to gluten, untreated celiac
disease can cause male infertility. Fertility may improve after
adopting a gluten-free diet.
Prostate infections. Past prostate
or other genital infections such as mumps or a sexually
transmitted disease can affect fertility.
Exposure to toxins. Examples
include heavy metals, industrial chemicals and radioactivity.
Exposure to certain drugs and
medications. Examples include cancer medications and anabolic
High temperatures. Exposing the
testicles to high temperatures — such as a hot tub or sauna —
can temporarily reduce fertility.
Previous vasectomy. Some men
who've had a vasectomy reversed remain infertile.
Many types of male infertility aren't preventable. However, there
are a few things that you can avoid that are known causes of male
Don't have a vasectomy. If there's
any possibility you'll want to father a child in the future, opt
for other forms of birth control. Even if reversed, a vasectomy
may still affect fertility.
Avoid illicit drugs. Use of
anabolic steroids, marijuana and cocaine can impair sperm
Don't drink too much alcohol.
Heavy drinking can impair fertility and sexual function. Drink
no more than two drinks a day.
If you smoke tobacco, quit.
Smoking is linked to impaired fertility.
Avoid exposure to heat. Steer
clear of extended or regular use of hot tubs, saunas and steam
baths. High temperatures are thought to temporarily impair sperm
Tests and Diagnosis
If you and your partner are unable to become pregnant within a
reasonable time, see your doctor. Some infertile couples have more
than one cause of their infertility. Your doctor will usually begin
a comprehensive infertility examination on both you and your
In some cases, the cause of your infertility may be unclear, or it
may take a number of tests to determine the cause. Infertility tests
can be expensive and may not be covered by insurance — find out what
your medical plan covers ahead of time.
For a man to be fertile, the testicles must produce enough healthy
sperm, and the sperm must be ejaculated effectively into the woman's
vagina. Tests for male infertility attempt to determine whether any
of these processes are impaired.
General Physical Examination and Medical History
This includes examination of your genitals and questions about
illnesses, disabilities and surgeries that could affect fertility.
Your doctor will want to know what medications you take and your
sexual habits. Your doctor may also ask about your sexual
development as a boy and whether you've had any signs of low
testosterone, such as decreased body or facial hair.
This is the most
important test for the male partner. Semen is generally obtained by
masturbating or by interrupting intercourse and ejaculating your
semen into a clean container. A laboratory analyzes the physical
characteristics of your semen, the number of sperm present and looks
for any abnormalities in the shape and structure (morphology) and
movement (motility) of the sperm. The lab will also check your semen
for signs of problems, such as infections or blood. Often sperm
counts fluctuate from one specimen to the next, so your doctor may
want to evaluate a few different samples. If your sperm analysis is
normal, your doctor will likely recommend thorough testing of your
female partner before conducting further male infertility tests.
Depending on initial findings, your doctor may recommend additional,
more specialized tests that can help identify the cause of your
infertility. These can include:
uses high-frequency sound waves to produce images of structures
within your body, can help your doctor look for evidence of a
varicocele or obstruction of the epididymis.
by the pituitary and hypothalamus glands and the testicles play a
key role in sexual development and sperm production. Your doctor may
recommend a blood test to determine the level of testosterone and
other male hormones that affect fertility. A number of infertility
problems can be caused by an underlying condition that affects
These tests are
used if your doctor suspects your fertility problems could be caused
by an inherited sex chromosome abnormality. When sperm concentration
is extremely low, genetic causes could be involved. A blood test can
reveal whether there are subtle changes in the Y chromosome.
This test involves
removing samples from the testicle with a needle. It may be used if
your semen analysis shows no sperm at all. The results of the
testicular biopsy will tell if sperm production is normal. If it is,
your problem is likely caused by blockage or another problem with
These tests are
used to check for immune cells (antibodies) that attack sperm and
can affect their ability to function. You are especially likely to
have anti-sperm antibodies if you've had vasectomy reversal.
In some cases,
contrast dye is injected into each vas deferens to see whether they
Sperm Function Tets
A number of
different tests can be used to evaluate how well your sperm survive
after ejaculation, how well they can penetrate the egg membrane, and
whether there's any problem attaching to the egg.
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