Med Clin N Am 88 (2004) 367–385

Male factor infertility

Evaluation and management
Victor M. Brugh, III, MDa, Larry I. Lipshultz, MDb,*
a
Department of Urology, Eastern Virginia Medical School, 400 West Brambleton
Avenue, Suite 100, Norfolk, VA 23510, USA
b
Division of Male Reproductive Medicine and Surgery, Scott Department of Urology,
Baylor College of Medicine, 6560 Fannin, Suite 2100, Houston, TX 77030, USA

Infertility affects over 6 million couples in the United States. Half of these
couples have a component of male factor infertility and almost 30% solely
are caused by a male factor [1]. In most communities, female partners
contact their gynecologist or primary care physician about fertility concerns,
which leads to the appropriate acquisition of a semen analysis from the male
partner. After identifying abnormal semen parameters, the care of a sub-
fertile male varies greatly, depending on the desires of the affected couple,
available resources, local referral patterns, and treatment style of the
involved physicians. The authors believe the most productive and cost-
effective therapy can be delivered only after a complete male factor
evaluation. Equally important is identifying potential significant and even
life-threatening medical pathology in these patients, which can present only
as infertility in 1.3% of infertile men [2]. This article reviews the evaluation
of the infertile male, discusses the etiology of testicular failure, and reviews
current treatment options. The discussion is divided into pretesticular,
testicular, and posttesticular causes of male infertility.

History and physical examination

The evaluation of the subfertile male begins with a detailed history and
physical examination. A reproductive history determines whether the couple
have conceived previously (secondary infertility) or if they are primarily
infertile. If either partner has conceived during a previous relationship, this
shifts the preliminary evaluation toward the other partner. The duration of

* Corresponding author.
E-mail address: larryl@bcm.tmc.edu (L.I. Lipshultz).

0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S0025-7125(03)00150-0
368 V.M. Brugh, III, L.I. Lipshultz / Med Clin N Am 88 (2004) 367–385

attempted conception is important in that a longer duration of infertility

carries a poorer prognosis. Other information important to the sexual
history includes intercourse timing and frequency; prior history of
reproductive tract infections; and the use of lubricants during intercourse,
which may impair sperm motility (K-Y jelly, Lubifax, Surgilube, hand
lotions, petroleum jelly, and saliva) [3]. Pediatric disorders and present
medical conditions can lead to impaired spermatogenesis or give clues
about a hormonal etiology for infertility. Prior scrotal, pelvic, or
retroperitoneal surgery may also obstruct the extratesticular ductal system
or affect ejaculation and result in inadequate sperm deposition into the
vagina. Alcohol and tobacco, environmental exposures at work, and some
medications, may be gonadotoxic and should be thoroughly investigated.
The physical examination should focus on the male body habitus to
identify whether the individual is appropriately virilized without evidence of
gynecomastia. A thorough genitourinary examination should be performed
identifying penile and scrotal pathology. The phallus should be examined for
hypospadias and skin lesions. Testicular size and shape, including masses,
should be carefully examined. Normal adult testicular size varies between 18
and 20 mL and small testes most likely indicate impaired spermatogenesis [4].
The presence of vasa and epididymis and epididymal induration or cysts
should be noted. Finally, the most common correctable cause for male in-
fertility, a varicocele [5], can be identified by careful palpation of the sper-
matic cords with and without the patient performing a Valsalva’s maneuver.

Laboratory evaluation
The laboratory evaluation of the infertile male begins with the semen
analysis. The semen analysis, however, is not a test of male fertility. First,
fertility is a couple-related phenomenon. A routine semen analysis tells one
very little about actual sperm function. Semen analyses should be collected
by masturbation after a 2- to 3-day period of abstinence. Long periods of
abstinence lead to decreased motility, and shorter periods result in low
volume and density. With the recommended intercourse frequency of every
other day, an abstinence period of 2 days reflects the semen parameters
available during attempted natural conception (Table 1).
Endocrine disorders have been identified in up to 20% of infertile men
[6]. Serum testosterone and follicle-stimulating hormone (FSH) identify
99% of all endocrine abnormalities in men with soft testes and less than
1 million sperm per milliliter. Other potentially useful hormone parameters
include luteinizing hormone (LH), prolactin, and estradiol, which should be
assayed contingent on findings during history, physical examination, and
initial hormone evaluation.
Azoospermia is the complete absence of sperm in the ejaculate and occurs
in 8% of infertile men. Azoospermia may be caused by obstruction of the
 V.M. Brugh, III, L.I. Lipshultz / Med Clin N Am 88 (2004) 367–385 369

Table 1
Normal semen parameters
Parameter Normal
Volume >2 mL
pH 7.2–7.8
Sperm concentration
20 million/mL
Total sperm count
40 million/mL
Motility
50% with normal morphology
Morphology
30% normal forms
Data from World Health Organization. WHO laboratory manual for the examination of
human semen and sperm-cervical mucus interaction. 4th edition. Cambridge, UK: New York,
NY: Published on behalf of the World Health Organization [by] Cambridge University Press;
1999.

extratesticular ductal system (obstructive azoospermia) or defects in

spermatogenesis (nonobstructive azoospermia). Men with obstructive
azoospermia typically have normal-sized testes, possible epididymal fullness,
and a normal serum FSH. Men with nonobstructive azoospermia present
frequently with small or soft testes and an elevated FSH. A critical compo-
nent of the evaluation of the azoospermic male is centrifugation of the
sample with microscopic examination of the pellet. Twenty-one percent of
men initially diagnosed with nonobstructive azoospermia have motile sperm
present in a centrifuged pellet of their semen; these men are not truly
azoospermic [7].
Patients with nonobstructive azoospermia should undergo genetic testing
(see later section) before proceeding to assisted reproductive techniques.
Between 40% and 60% of these men have sperm present in the testes, and
these sperm can be used for in vitro fertilization (IVF) with intracytoplasmic
sperm injection (ICSI). Testis biopsy should not be used only as a diagnostic
modality in these men, but should also be a therapeutic maneuver for sperm
retrieval (testicular sperm extraction). Testis biopsy for purely diagnostic
purposes is recommended only when a diagnosis of obstruction or partial
obstruction is suspected. In these cases normal spermatogenesis confirms
obstruction.

Pretesticular causes of male infertility

Endocrinopathies
The hypothalamic–pituitary–gonadal (HPG) axis is a complex integrated
system that is necessary for normal reproduction. The hypothalamus is the
center of the reproductive hormonal axis because it receives input from
many regions within the brain and feedback in the form of steroid and
protein hormones from both the gonads and adrenal glands. The hypotha-
lamus releases gonadotropin-releasing hormone (Gn-RH) from the preoptic
370 V.M. Brugh, III, L.I. Lipshultz / Med Clin N Am 88 (2004) 367–385

and arcuate nuclei as the end result of its integrative function. Gn-RH, in
turn, is secreted in a pulsatile fashion into the portal hypophyseal venous,
which feeds the anterior pituitary. Gn-RH stimulates the release of LH and
FSH from the anterior pituitary gland. LH release is modulated by feedback
of androgens at both the pituitary and hypothalamic levels. The release of
FSH seems to be regulated further by negative feedback of both inhibin and
activin from Sertoli’s cells of the testis. In the testis, LH stimulates
testosterone production by Leydig’s cells, whereas FSH is crucial to the
initiation and maintenance of spermatogenesis. Both LH and FSH are
necessary for quantitatively normal spermatogenesis. Feedback within this
axis is essential for normal function and it occurs at multiple levels, allowing
for precise regulation of hormonal activity. Abnormalities anywhere in the
HPG axis have the potential for a negative impact on fertility in the male. In
general, endocrine defects leading to male infertility can be evaluated
initially by assaying testosterone, LH, FSH, prolactin, and estradiol.

Genetic endocrinopathies
Genetic abnormalities can cause hormone, growth factor, and receptor
dysfunction affecting the HPG axis [8]. The following disorders are un-
common, but may severely impair male fertility. These disorders usually are
caused by mutations, small deletions, or polymorphic expansions within
specific genes involved in the endocrine or humoral regulation of sexual devel-
opment and function.

Disorders of production or secretion of gonadotropin-releasing hormone

Disorders resulting in abnormal synthesis and release of Gn-RH and
subsequent low levels of FSH and LH without an anatomic cause are termed
‘‘idiopathic hypogonadotropic hypogonadism’’ [8]. Without adequate levels
of gonadotropins, androgen production and spermatogenesis fail.
Kallmann’s syndrome is the most common X-linked disorder in male
infertility and occurs in approximately 1 in 10,000 to 1 in 60,000 live births
[9]. A mutation in the Ka1 gene (Xp22.3) results in a deficiency in Gn-RH
secretion from the hypothalamus [10]. Many patients with Kallmann’s
syndrome are tall, anosmic, and present secondary to failure of pubertal
initiation. Because of the lack of FSH and LH stimulation of the testis,
spermatogenesis is absent, as is testosterone production, and these men have
firm prepubertal-sized testes and a small penis. Patients may also have
congenital deafness, asymmetry of the cranium and face, cleft palate,
cerebellar dysfunction, cryptorchidism, or renal abnormalities. Fertility can
be achieved in many Kallmann’s syndrome patients with a combination of
hormone replacement therapies (human chorionic gonadotropin and FSH)
[3]. Other defects in Gn-RH secretion or the Gn-RH receptor lead to
idiopathic hypogonadotropic hypogonadism that can be treated with
replacement of FSH and human chorionic gonadotropin (Table 2).
 V.M. Brugh, III, L.I. Lipshultz / Med Clin N Am 88 (2004) 367–385 371

Table 2
Genetic disorders leading to male infertility and treatment
Disorder Cause Treatment
Disorders of GnRH
secretion
Kallman’s syndrome Mutation in Kal gene Replacement of FSH
(Xp22.3) resulting in and HCG
#GnRH secretion
GnRH receptor defects Defects in G-protein Replacement of FSH
coupled for GnRH and HCG
#GnRH secretion Mutation in Convertase-1 Replacement of FSH
gene (PC1) and HCG
Prader-Willi syndrome Mutation in 15q11q13 Replacement of FSH
and HCG
Disorders of LH and Defects in LH or FSH Replacement of FSH
FSH function structure or receptor and HCG if LH or
defects FSH structural defect
Disorders of androgen
function
Congenital adrenal Mutations in Replacement of
hyperplasia steroidogenic enzymes corticosteroids,
mineralocorticosteroids,
or androgens
Androgen insensitivity Mutations in the androgen These men may be
(Reifenstein’s syndrome, receptor gene candidates for
testicular ferminization, TESE-IVF-ICSI
Lub syndrome, although success rates for
Rosewater’s syndrome) sperm extraction have not
Kennedy’s syndrome Expansion of the been reported nor have
polyglutamine tract outcomes of IVF-ICSI
in the AR
transactivation domain
5a-Reductase deficiency Mutations in the
5a-reductase gene
Abbreviations: FSH, follicle-stimulating harmone; GnRH, gonadotropin-releasing hor-
mone; HCG, human chorionic gonadotropin; ICSI, intracytoplasmic sperm injection; IVF, in
vitro fertilization; LH, levtinizing hormone; TESE, testicular sperm extraction.
Data from Refs. [11–15,17,76–78].

Disorders of leutinizing hormone, follicle-stimulating hormone, and

androgen function
Leutinizing hormone and FSH are released from the pituitary under the
influence of pulsatile stimulation of Gn-RH. Mutations resulting in
biologically inactive LH or FSH are caused by abnormalities in FSH or
LH structure or FSH or LH receptor activity. These abnormalities result in
a spectrum of disease from complete virilization failure to less severe
hypogonadism [11–13]. LH drives androgen production. Androgen synthe-
sis and metabolism is a complex, stepwise process, and mutations in the
enzymes involved in this biosynthesis influence male reproductive function.
Five enzymes are required for the synthesis of testosterone from cholesterol.
372 V.M. Brugh, III, L.I. Lipshultz / Med Clin N Am 88 (2004) 367–385

Mutations in these enzymes lead to congenital adrenal hyperplasia resulting

in phenotypes ranging from incomplete virilization to completely feminized
genitalia with cryptorchid testes [14].
Testosterone is metabolized to dihydrotestosterone by 5a-reductase in the
external genitalia and prostate. Mutations in the 5a-reductase gene lead to
incomplete development of the external genitalia [14], and infertility follows
because of the inability effectively to deliver sperm.
Testosterone and dihydrotestosterone freely diffuse into all cells, al-
though they can be delivered to the nucleus only by androgen receptors
to affect cellular activity. Defects in the androgen receptor gene (AR)
defunctionalize this receptor and may cause a wide range of internal and
external virilization abnormalities. These abnormalities include androgen
insensitivity syndromes, such as Reifenstein’s syndrome; testicular femini-
zation; Lub syndrome; and Rosewater’s syndrome [15]. Clinically, androgen
insensitivity causes a range of phenotypes. Ambiguous genitalia, micropenis,
and hypospadias result from partial androgen responsiveness, whereas
complete androgen insensitivity leads to a female phenotype with intra-
abdominal testis [16].
Another form of androgen insensitivity is associated with an adult-onset
motor neuron disease. Spinal and bulbar muscular atrophy, or Kennedy’s
syndrome, is an X-linked genetic disease associated with an expansion of
a polyglutamine tract within the AR transactivation domain. Patients with
Kennedy’s syndrome have a progressive weakness in the proximal spinal and
bulbar muscles with associated gynecomastia, testicular atrophy, and sper-
matogenic impairment. Symptoms typically begin during midlife, and with
each subsequent generation the onset and severity of disease worsens. This is
caused by lengthening of the CAG (cytosine, adenosine, and guanine) tract,
a process referred to as anticipation [17].
Testing for subtle genetic endocrinopathies, however, is not widely avail-
able. Males suspected to have Kallman’s syndrome may be evaluated for
Kal mutations; otherwise, specialized genetic testing is not usually performed.

Nongenetic endocrinopathies
Adenomatous growth of the pituitary gland is another uncommon but rec-
ognized cause of male infertility. Pituitary masses can interfere with the release
of gonadotropins either by direct compression of the portal system or
by decreased FSH-LH secretion resulting in hypogonadotropic hypogonad-
ism. In patients with decreased testosterone levels in the setting of low LH,
one must consider a pituitary adenoma and a MRI of the head is essential.
Hyperprolactinemia can also be seen in association with adenomas of the
pituitary. Elevated prolactin interferes with the normal pulsatile release of
Gn-RH and can itself be a cause of hypogonadism with subsequent sexual
dysfunction and infertility. Surgery, radiation, and medical treatment
have all been used as effective treatment with cabergoline (Dostinex) and
 V.M. Brugh, III, L.I. Lipshultz / Med Clin N Am 88 (2004) 367–385 373

bromocriptine (Parlodel) as the mainstays of medical therapy. Iatrogenic

causes of hyperprolactinemia include the selective serotonin reuptake
inhibitors, which have become widely prescribed for numerous mental health
conditions. In general, evaluation of the pituitary with MRI is only warranted
when symptoms or routine hormone studies suggest pituitary disease.
It is well understood that administration of exogenous androgen causes
a suppression of endogenous testosterone production. Anabolic steroid use
results in negative feedback at the level of the hypothalamus and pituitary,
and LH release is reduced as part of the HPG axis feedback mechanism.
Normal spermatogenesis requires adequate intratesticular testosterone; in
patients using steroids, sperm production is significantly reduced and
azoospermia is often seen. The extent and reversibility of the detrimental
effect of steroids on spermatogenesis are dependent on dose and duration of
exogenous steroid use.
Testosterone is metabolized to estradiol by aromatase. Recent inves-
tigations have revealed that some men with poor sperm concentration and
motility may have decreased testosterone:estradiol ratios. In those patients
treatment with oral aromatase inhibitors (anastrozole [Arimidex] and
letrozole [Femora]) has resulted in statistically significant increases in sperm
concentration and motility [18].

Testicular causes of male infertility

Varicocele
Varicoceles are a common entity found in 15% of the general male
population [19], although among men with primary infertility the incidence
increases to approximately 40% [20], and 45% to 81% of men with
secondary infertility have varicoceles [21], making varicoceles the most
common correctable cause of male infertility. Varicoceles are dilated internal
spermatic veins, which along with the cremasteric and vasal veins drain the
testis. These dilated veins are found more commonly on the left or bilaterally
than on the right alone [22] and are thought to be secondary to incompetent
venous valves. There are several theories on the pathophysiology of
varicoceles leading to male subfertility. One theory is that poor venous
drainage disrupts the countercurrent exchange of heat in the spermatic cord
or increases testicular perfusion allowing a rise in scrotal temperature [23].
Elevated scrotal temperatures subsequently lead to impaired spermatogen-
esis [24]. Another theory is that cellular metabolites acting as gonadotoxins
are poorly drained from the testis and lead to impaired spermatogenesis [25].
Men with varicoceles have also been found to have abnormal testosterone
concentrations, which improve after varicocele repair, suggesting a possible
hormonal etiology of impaired spermatogenesis [26,27].
Varicocele repair is indicated for men with pain associated with the
varicocele, testicular atrophy, or infertility that is not attributable to any
374 V.M. Brugh, III, L.I. Lipshultz / Med Clin N Am 88 (2004) 367–385

other causes. Varicoceles can be corrected by surgical ligation of the dilated

internal spermatic veins or radiographic embolization of these veins.
Currently, most male reproductive surgeons use a microsurgical technique
sparing the internal spermatic arteries and lymphatics. In a review by Pryor
and Howards [20] varicocele repair improved semen quality in 51% to 78%
of patients and 24% to 53% of patients initiated spontaneous pregnancies
after varicocele repair. Prospective randomized trials of varicocele repair
have been few, but Madgar et al [28] reported that 71% of men undergoing
varicocele repair attained spontaneous pregnancy verses 10% spontaneous
pregnancy rate in men randomized to ‘‘no therapy’’ in a prospective,
randomized crossover trial. Most notably, improvement in sperm density,
motility, and pregnancy rates has been reported. In addition, improvements
in sperm strict morphology [29–31], the sperm penetration assay [32], and
seminal reactive oxygen species have recently been described following
varicocele repair [33]. Finally, return of sperm to the ejaculate has been
reported for some azoospermic men after varicocele repair [34–36].
Varicocele repair offers subfertile couples not only improved rates of
spontaneous pregnancy but improvement of semen quality that can shift
the level of assisted reproductive technology (eg, IVF to intrauterine
insemination) necessary to attain pregnancy. Correcting a varicocele often
proves to be a cost-effective treatment [37,38]. In a study of 540 infertile men
with varicoceles, Cayan et al [37] found 31% of men requiring ICSI or IVF
(total motile sperm count \5 million) to treat their infertility had
improvement in semen quality after varicocele repair to allow intrauterine
insemination or spontaneous pregnancy (total motile sperm count >5
million). These findings were in addition to a 36.6% spontaneous pregnancy
rate. In another study Schlegel [38] evaluated the cost effectiveness of
varicocele repair versus IVF and ICSI. Using a delivery rate of 42.2% and
estimated cost of successful delivery of $62,263 for IVF and ICSI, varicocele
repair was markedly more cost effective with a delivery rate of 30% and cost
of $26,268. Varicocele repair also avoids IVF-related complications, such as
multiple gestation and ovarian hyperstimulation, and allows the possibility
of more than one natural pregnancy with a single therapy [38].

Genetics
A genetic disorder may alter spermatogenesis, impair normal develop-
ment of the genital tract, and decrease sperm motility and fertilization
capacity, any of which may lead to varying degrees of male subfertility or in-
fertility. Genetic disorders may be characterized as karyotype abnormalities,
deletions of specific areas of chromosomes involved in the regulation of sper-
matogenesis, or specific mutations within genes.
Karyotype abnormalities are more common in infertile males (5.8%) than
in a normal population of newborn males (0.5%) [39]. Sex chromosome
abnormalities are more common (4.2%) than autosomal chromosome
 V.M. Brugh, III, L.I. Lipshultz / Med Clin N Am 88 (2004) 367–385 375

abnormalities (1.5%). Chromosome defects are subcategorized as either

numerical or structural. Numerical chromosome abnormalities include
deletion or duplication of whole chromosomes. Structural chromosome
abnormalities include deletion, inversion, or duplication of a portion of
a chromosome or translocation of part of a chromosome to another
chromosome. Structural and numerical chromosome abnormalities are
observed in some patients with azoospermia and severe oligozoospermia and
involve the autosomes, sex chromosomes, or both.
Klinefelter’s syndrome (47,XXY) is the most common sex chromosome
disorder, occurring 30 times more frequently in infertile men attending an
infertility clinic [40]. Klinefelter patients are azoospermic or severely
oligospermic [41], and account for approximately 14% of all cases of
azoospermia [42]. The phenotype of males with Klinefelter syndrome varies,
but can include small firm testes, increased height, female hair distribution,
lower extremity varicosities, decreased level of intelligence, diabetes mellitus,
obesity, increased incidence of leukemia and nonseminomatous extragonadal
germ cell tumors, and infertility [43]. The patients with gynecomastia have an
increased risk of developing breast cancer. Ten percent of Klinefelter patients
are 46,XY/47,XXY mosaic and have a less severe phenotype [42]. These
patients have a variable level of sperm production but rarely achieve paternity
through natural conception [44]. Other less common sex chromosomal
abnormalities include mixed gonadal dysgenesis, XX males, and XYY males,
and are reviewed in Table 3.
The Y chromosome plays a major role in male reproductive function.
First, the testis-determining factor (SRY), a critical region for normal male
development, is found on the short arm of the Y chromosome (Yp) [45]. The
azoospermia factor region (AZF) of the Y chromosome is also required for
normal spermatogenesis and is located on the long arm of the Y chromosome
(Yq11) [46]. Three nonoverlapping intervals within the AZF region (AZFa,
AZFb, and AZFc) have been identified, and microdeletions involving these
regions are found in some infertile men. Genes in these regions seem to code
for proteins involved in the regulation of spermatogenesis. The reported

Table 3
Sex chromosome abnormalities leading to male infertility
Syndrome Karyotype abnormalities Phenotype
Klinefelter’s syndrome 46,XY/47,XXY mosaic, Male with increased height,
47,XXY–49,XXXY small firm testes, possibly
female hair distribution
Mixed gonadal 45,X/46,XY mosaic, possibly Male, female, or ambiguous
dysgensis normal 46,XY genitalia, testis, and streak
gonad
XX male syndrome 46,XX SRY translocation to Male with Sertoli’s-cell-only on
the short arm of X testis biopsy
XYY male 47,XYY Male, possibly increased height
376 V.M. Brugh, III, L.I. Lipshultz / Med Clin N Am 88 (2004) 367–385

incidence of Y-chromosome microdeletions varies from study to study

depending on patient selection criteria. Overall, 4% of oligospermic men are
found to have Y-chromosome microdeletions, and the incidence rises to 18%
in idiopathic azoospermic men [47]. To identify Y-chromosome micro-
deletions, most laboratories use a polymerase chain reaction assay and gel
electrophoresis.
The incidence of karyotype abnormalities and Y-chromosome micro-
deletion increases as the sperm density decreases. The authors recommend
high-resolution banding cytogenetic analysis and Y-chromosome micro-
deletions for all men with sperm densities below 5 million per milliliter,
especially those contemplating the use of assisted reproductive techniques.
Infertile patients with abnormal karyotypes or Y-chromosome micro-
deletions may have a few sperm in their ejaculate or within the testis. These
sperm may be used with ICSI-IVF. Successful pregnancies have been
achieved with sperm harboring abnormal karyotypes and Y-chromosome
microdeletions using these techniques. Children of fathers with karyotype
abnormalities may be normal. Because of the risk of unbalanced trans-
locations occurring during meiosis, however, some of these children may be
malformed and may not survive [44,48]. Male offspring born to fathers with
Y-chromosome microdeletions are expected to inherit these microdeletions
[49]. A couple with a male partner found to have an abnormal karyotype or
Y-chromosome microdeletion should undergo genetic counseling before
attempting to achieve a pregnancy.

Cryptorchidism
The incidence of cryptorchidism at 1 year of age is 0.8% [50]. Many of
these men are subfertile, although the exact pathophysiology of the resultant
infertility has not been defined. Two possible etiologies for infertility in these
patients exist. The first is that the anatomic location of the testis outside of the
scrotum results in impaired spermatogenesis. Cryptorchid testes reveal
smaller seminiferous tubules, decreased numbers of spermatogonia, and
thickened basement membranes by 1.5 years of age [51]. If left in a crypt-
orchid location, 69.2% of testes have a Sertoli’s-cell-only histology when
removed postpubertally [52]. Cryptorchid males also have a poor response
to Gn-RH stimulation and lower basal levels of LH and testosterone [53].
If left untreated, 50% to 70% of unilateral cryptorchid men are oligospermic
or azoospermic and almost all bilaterally cryptorchid men are azoospermic
[54]. Of men who underwent orchidopexy before puberty 62% and 30% had
sperm densities greater than 20 million sperm per milliliter for unilateral
and bilateral cryptorchidism, respectively [55]. Azoospermic men can under-
go testicular sperm extraction for sperm retrieval to be used in IVF-ICSI
cycles. At the time of testicular sperm extraction the authors recommend
obtaining a testicular biopsy for pathologic review to rule out carcinoma
in situ.
 V.M. Brugh, III, L.I. Lipshultz / Med Clin N Am 88 (2004) 367–385 377

Exposure to gonadotoxins
Numerous substances and occupations have been implicated to decrease
semen quality. These potential gonadotoxins have been difficult to study
because of sample size and confounding factors that are hard to control. A
list of gonadotoxins follows. The effects of these agents are reversible if the
offending agent is removed or activity ceased before the decline of the semen
quality to azoospermia.
Drugs
Cimetidine
Sulfasalazine
Nitrofurantoin
Anabolic steroids
Narcotics
Chemotherapeutics
Chemicals
Organic solvents
Pesticides
Heat
Welders or ceramics workers
Repeated or prolonged hot tub use
Radiation
Therapeutic radiation
Nuclear power plant workers
Heavy metals
Battery manufacturing
Printing
Marijuana or tobacco use
Alcohol use
Radiation and chemotherapy can permanently damage the germinal
epithelium leading to variable recovery of spermatogenesis. It is strongly
recommended that patients bank their semen before initiating therapy in an
effort to preserve their fertility. After chemotherapy, men are asked not to
conceive for 2 years, at which time a semen analysis should be obtained if
the patient is unable to conceive in a timely manner. Azoospermic men after
chemotherapy have a 41% of having sperm present in the testis to be used in
IVF-ICSI cycles with testicular sperm extraction [56].

Posttesticular causes of male infertility

Obstruction
Obstruction of the excretory ductal system can occur along the
ejaculatory ducts, vas deferens, epididymis, or ejaculatory ducts. History,
378 V.M. Brugh, III, L.I. Lipshultz / Med Clin N Am 88 (2004) 367–385

physical examination, semen parameters, and radiologic studies can be used

to identify the location of the obstruction. Vasal obstruction may be caused
by inguinal or pelvic surgery. Scrotal surgery, such as prior spermatocelect-
omy, orchidopexy, or hydrocelectomy, may result in epididymal obstruc-
tion. Recurrent bouts of epididymitis may lead to epididymal obstruction.
On physical examination, the absence of the vas deferens is found in patients
with congenital bilateral absence of the vas deferens (CBAVD), and dilated
epididymis indicates possible obstruction.
Semen analysis varies with the site of obstruction. Complete ejaculatory
duct obstruction results in a low-volume, acidic, fructose-negative ejaculate.
Obstruction of the vasa or epididymis results in a normal-volume, basic,
fructose-positive ejaculate. Men with obstruction as the only cause for their
infertility have a normal testosterone and FSH. Radiographic studies are
necessary when obstruction of the excretory ducts is suspected. Transrectal
ultrasound supports the diagnosis of ejaculatory duct obstruction by
identifying dilated ejaculatory ducts and seminal vesicles and cystic masses
and stones causing obstruction. A transrectal aspirate of dilated seminal
vesicles during transrectal ultrasound that reveals numerous sperm is also
evidence that ejaculatory duct obstruction is present. Absence of seminal
vesicles or hypoplastic seminal vesicles on transrectal ultrasound are
confirmatory of CBAVD. If vasal occlusion is suspected, a vasogram
during scrotal exploration confirms the diagnosis and identifies the site of
obstruction. Threading a 1-0 nylon suture through the abdominal vas at the
time of vasography determines the exact distance from the vasostomy to the
site of obstruction. The treatment of choice for ejaculatory duct obstruction
is transurethral resection of the ejaculatory ducts. Approximately half of the
men undergoing this procedure for ejaculatory duct obstruction have
improvement of their semen parameters and half of the men who improve
achieve a subsequent pregnancy [57]. Men with vasal obstruction or
obstruction at the epididymis are candidates for microsurgical reconstruc-
tion to allow natural conception or microsurgical epididymal sperm
aspiration for sperm retrieval to be used with IVF-ICSI.
Congenital bilateral absence of the vas deferens is the most frequently
found obstruction of the extratesticular ductal system, affecting 1% to 2%
of infertile men [58]. CBAVD is part of the phenotypic spectrum of cystic
fibrosis (CF), an autosomal-recessive disease, of which 1 in 25 whites are
carriers [58]. CF is caused by a genetic mutation of the CF transmembrane
conductance regulator gene (CFTR). The CFTR gene is large (250,000 base
pairs), and to date more than 1000 CFTR mutations have been identified.
Characteristics of men with CBAVD include absence of the vas deferens;
hypoplastic, nonfunctional seminal vesicles and ejaculatory ducts; and an
epididymal remnant, frequently composed of only the caput region that is
firm and distended [59]. Spermatogenesis is not impaired in these patients;
sperm may be harvested from the epididymis (microsurgical epididymal
sperm aspiration) for use in ICSI-IVF, allowing affected couples to achieve
 V.M. Brugh, III, L.I. Lipshultz / Med Clin N Am 88 (2004) 367–385 379

a pregnancy. Men with CBAVD and their wives should be screened for
CFTR mutations and referred to genetic counseling before sperm retrieval.
Routine analysis of the CFTR gene is available from most genetic
laboratories. Only about 30 mutations, of the possible 1000, are regularly
screened for in the clinical diagnostic laboratory, so a specific mutation may
be present that is not identified. Absence of a mutation in these limited
assays does not guarantee that an offspring will not be born with CF if the
wife is also a carrier. In addition to the 1000 known mutations in this gene,
there is a polymorphism in intron 8 (noncoding region) that quantitatively
influences the production of the CFTR gene product. The alleles of this
polymorphic region of thymidines in intron 8 of the CFTR gene contain five
(5T), seven (7T), or nine (9T) thymidines. The 5T allele results in the least
efficient processing of the CFTR mRNA. The 5T mutations lead to a lower
amount of protein production and increased severity of the observed
phenotype [59]. A separate analysis must be ordered to assess this most
common polymorphism (5T); however, this test is not routinely run in all
clinical laboratories performing routine CF gene analysis, reinforcing the
limits associated with a negative result. Because of the many variable
mutations and difficulty identifying all possible mutations in a single patient,
all patients with CBAVD are now thought to have a genetic form of CF [59].
Men with idiopathic epididymal obstruction have also been found to have
an increased incidence of CF mutations. These men should also undergo CF
testing before reconstruction or microscopic epididymal sperm aspiration.
Finally, patients presenting with unilateral absence of the vas deferens are
also considered at risk and should undergo analysis of the CFTR gene,
although unilateral absence of the vas deferens in a patient with a con-
tralateral solitary kidney may represent a different congenital anomaly.

Immunologic infertility
Nine percent to 33% of infertile couples are found to have antisperm
antibodies. In 8% to 19% of these couples the antibodies are present in the
man and in 1% to 21% antisperm antibodies are contributed by the female
partner [60–62]. Risk factors for the formation of antisperm antibodies in
men include vasectomy and epididymitis [63,64], although the exact cause
for formation of antisperm antibodies is frequently unclear.
Typically, mature sperm are not identified as self. Sperm are not formed
until puberty, long after immunologic tolerance to autoantigens has been
developed. Secondary spermatocytes and maturing sperm are isolated from
immune cells in the luminal compartment of the seminiferous tubule by
Sertoli’s cell tight junctions (the blood-testis barrier). It is also believed that
small leakage of sperm-specific antigens causes a late tolerance to these anti-
gens [65] and may also contribute to the prevention of antisperm antibodies.
Antisperm antibodies may decrease fertility potential at several critical
points that are important to natural conception. Antisperm antibodies cause
380 V.M. Brugh, III, L.I. Lipshultz / Med Clin N Am 88 (2004) 367–385

sperm cells to agglutinate, hindering sperm motility [66]. Sperm penetration

through the cervical mucus is also impaired [67]. Sperm with antisperm
antibodies also have poor sperm-egg interactions. The acrosome reaction
[68] and zona pellucida binding [69] may be impaired, which in turn may
decrease overall fertility potential.
Antisperm antibodies are most commonly detected using either the
immunobead assay or SpermMAR assay. When antisperm antibodies have
been detected in an infertile couple, there are numerous treatment options.
First, men with genitourinary infections, including epididymitis or prosta-
titis, should be treated with appropriate antibiotics, and men with ductal
obstruction should be counseled regarding surgical reconstruction. When a
specific cause for antisperm antibodies cannot be identified other therapies
include immunosuppression with steroids, sperm processing with intrauter-
ine insemination, and IVF with ICSI [70–72].

Disorders of ejaculation
Ejaculation consists of the coordinated deposition of semen into the
prostatic urethra (emission), closure of the bladder neck, and contraction of
the periurethral and pelvic floor muscles causing expulsion of the semen
through the urethra (ejaculation). The process of ejaculation is dependent
on central and peripheral nervous system control. Emission is controlled by
sympathetic neurons originating from T10-L3 that travel through the
paravertebral sympathetic ganglia. Ejaculation requires somatic motor inner-
vation from S2-4 and continues through the pudendal nerves to the bladder
neck and pelvic floor musculature.
Abnormalities of ejaculation can lead to lack of emission ejaculation and
retrograde ejaculation and may be caused by neurologic, anatomic, and
psychologic conditions. Retrograde ejaculation is caused by incomplete
closure of the bladder neck. Diabetes mellitus causes peripheral nervous
system injury resulting in possible retrograde ejaculation or anejaculation.
Failure of emission or ejaculation can also be caused by excision of a portion of
the sympathetic chain or pelvic nerves during retroperitoneal lymph node
dissection for testicular cancer or other retroperitoneal, abdominal, or
pelvic surgery. Central nervous system lesions, such as spinal cord injury
and myelodysplasia, can also cause ejaculatory dysfunction. Finally, some
medications affect ejaculation, such as a-blockers (causing retrograde
ejaculation); antidepressants; antipsychotics; and some antihypertensives.
Anatomic causes for ejaculatory dysfunction include obstruction of the
ejaculatory ducts and prior surgery on the bladder neck (Y-V plasty of the
bladder neck, transurethral incision, or resection of the prostate) leading to
retrograde ejaculation.
Treatment of ejaculatory disorders may be medical or surgical. Neurologic
causes of failure of emission, ejaculation, and retrograde ejaculation can be
treated with sympathomimetic agents that enhance emission and close the
 V.M. Brugh, III, L.I. Lipshultz / Med Clin N Am 88 (2004) 367–385 381

bladder neck. These medications include imipramine hydrochloride and

pseudoephedrine hydrochloride. If conversion from retrograde to antegrade
ejaculation fails, functional sperm may be retrieved from the bladder and
used for intrauterine insemination or IVF cycles. Other techniques to attain
semen from men with ejaculatory dysfunction include vibratory stimulation
and electroejaculation. Vibratory stimulation requires the use of a vibrator to
induce ejaculation and requires an intact reflex arc within the thoracolumbar
spinal cord [73]. The best predictors of success using this technique include
reflex hip flexion when the soles of the feet are scratched [74] and an intact
bulbocavernosus reflex [75]. Men who fail both medical therapy and
vibratory stimulation may proceed to electroejaculation.

Summary
There is a male factor involved in up to half of all infertile couples.
Potential etiologies in male factor infertility are many and require thorough
evaluation for their accurate identification. A complete medical history in
conjunction with a focused examination can allow for an appropriate choice
of laboratory and imaging studies. The semen analysis is a crucial first step,
but by no means is it sufficient to determine a specific etiology or dictate
therapy. A systematic approach is necessary to help guide the work-up and
rule out less likely causes. The etiologies discussed within this article are
tremendously broad, and the prognosis for any given couple depends, in large
part, on the etiology. Without a firm understanding of the genetics, anatomy,
physiology, and complex interplay of the male reproductive system, the
evaluation becomes an inefficient exercise that often fails to define the precise
etiology. Couples with male factor infertility need a systematic approach with
the efficiency of ultimate treatment determined largely by the physician’s
ability to identify the specific cause of the man’s reproductive failure.

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