Approach To The Male With Infertility

18/5/23, 18:43 Approach to the male with infertility - UpToDate
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Approach to the male with infertility

AUTHORS: Bradley D Anawalt, MD, Stephanie T Page, MD, PhD
SECTION EDITORS: Peter J Snyder, MD, Alvin M Matsumoto, MD
DEPUTY EDITOR: Kathryn A Martin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2023.

This topic last updated: Oct 04, 2022.
INTRODUCTION
Infertility in a couple is usually defined as the inability to achieve conception despite one year of
regular, unprotected intercourse. When the female partner is >35 years old, infertility is defined
as failure to conceive within six months of unprotected intercourse [1]. However, up to 40 to 50
percent of young, healthy couples that fail to conceive in the first 12 months will conceive in the
subsequent 12 months with no specific treatment [2,3]. Therefore, in some circumstances, delay
in extensive evaluation and treatment is reasonable. In approximately 35 percent of couples with
infertility, a male factor is identified along with a female factor; in approximately 10 percent, a
male factor is the only identifiable cause.
While many men with male infertility have oligozoospermia (a low number of sperm cells in the
ejaculate compared with reference ranges) or azoospermia (no sperm cells in the ejaculate),
some infertile men have normal sperm counts. Over 80 percent of infertile men have low sperm
concentrations and poor sperm quality (a decrease in sperm motility [asthenozoospermia]
and/or an increase in spermatozoa with abnormal morphology [teratozoospermia]). A small
percentage of infertile men have normal sperm concentrations but poor sperm quality, and
another small percentage of infertile men have normal sperm concentrations and normal
motility and morphology.
This topic will review the evaluation of male infertility. The causes and management of male
infertility and an overview of infertility are reviewed separately. (See "Causes of male infertility"
and "Treatments for male infertility".)
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CATEGORIES OF MALE INFERTILITY
The causes of male infertility can be divided into four main areas ( table 1) (see "Causes of
male infertility"):
● Endocrine and systemic disorders with hypogonadotropic hypogonadism – 5 to 15

percent.
● Primary testicular defects in spermatogenesis – 70 to 80 percent. Klinefelter syndrome

is the most common identifiable cause of a primary testicular defect, but the majority (90
to 95 percent) in this category have idiopathic dysspermatogenesis, an isolated defect in
spermatogenesis without an identifiable cause.
● Sperm transport disorders – 2 to 5 percent.
● Idiopathic male infertility – 10 to 20 percent. Idiopathic male infertility should be

distinguished from idiopathic dysspermatogenesis. Idiopathic male infertility describes an
infertile man with a normal semen analysis and no apparent cause for infertility, whereas
infertile men with idiopathic dysspermatogenesis have abnormal semen analyses.
The precise epidemiology of prevalence and causes of male infertility has never been accurately
assessed for several reasons, including differences in definitions of infertility, underreporting,
and lack of systematic data gathering [4,5]. The above prevalences are estimations of the
proportion of men presenting for infertility treatment at a referral center and likely do not
represent the prevalence in the broader community in industrialized countries, nor do these
estimations reflect likely regional variations around the world [4-6].
DIAGNOSTIC APPROACH
The initial evaluation of the male with infertility is focused on detecting the small percentage of
causes that can be treated to restore normal fertility. The remainder of the evaluation of male
infertility is focused on determining which couples with male factor infertility might benefit from
assisted reproductive technologies (ART).
Molecular biology techniques have increased the ability to identify more genetic causes of male
infertility, but only a minority of infertile men have an identifiable cause (see "Causes of male
infertility"). The disorders in many infertile men are characterized primarily by descriptions of
observed abnormalities, such as decreased sperm number, movement, or egg-penetrating and
fusion capabilities. Even testicular biopsies rarely shed insight on the underlying etiology; they
simply indicate the extent of spermatogenic impairment.
The essential components of the evaluation of the infertile man include (see 'Initial visit' below):
● History
● Physical examination
● Semen analysis; if abnormal, it should be repeated
Additional components of the evaluation of the infertile man may include (see 'Additional
evaluation' below):
● Endocrine testing
● Imaging of accessory glands and ducts
● Genetic tests
The profile created by the results permits a systematic assessment of the male partner.
Initial visit
History and physical examination — The evaluation of an infertile man should begin with a
detailed history that focuses on potential causes of infertility. A detailed history of the female
partner should also be obtained, including menstrual history, history of previous fertility (or
infertility), and any prior evaluation or treatment of infertility. For the male partner, the clinician
should inquire about symptoms, prior illnesses, trauma, surgical procedures, or exposure to
testicular toxins that are associated with male hypogonadism (dysspermatogenesis with or
without decreased testosterone production):
● Sexual developmental history, including testicular descent, pubertal development, loss of

body hair, or decrease in shaving frequency.
● Chronic severe systemic illness or history of major head trauma, surgery, or irradiation that
could result in hypogonadotropic hypogonadism. (See "Causes of secondary
hypogonadism in males".)
● Infections, such as mumps orchitis, sinopulmonary symptoms, sexually transmitted

infections, and genitourinary tract infections (including prostatitis).
● Surgical procedures or significant trauma involving the pelvis and genital area.
● Drugs and environmental exposures that can adversely impact the hypothalamic-pituitary-
testicular axis, including alcohol, tobacco, marijuana, opioids, radiation therapy, anabolic
steroids, corticosteroids, cytotoxic chemotherapy (current or past), drugs that cause

hyperprolactinemia, and exposure to toxic chemicals (eg, pesticides). (See "Causes of
secondary hypogonadism in males".)
● Sexual history, including libido, frequency of intercourse, and previous fertility assessments
of the man and his partner.
The physical examination should include a general medical examination to determine overall
health, obesity, and overt signs of endocrinopathies that are uncommon causes of male
infertility (eg, thyroid dysfunction or Cushing's syndrome).
Because some infertile men have combined defects in testosterone and sperm production, the
examination should also focus on findings suggestive of androgen deficiency. The clinical
manifestations of androgen deficiency depend upon the age of onset. Androgen deficiency
during early gestation presents as atypical genitalia; in late gestation as micropenis; in
childhood as delayed pubertal development; and in adulthood as decreased sexual function,
infertility, and, eventually, loss of secondary sex characteristics. The examination of the man
should include the following components. (See "Clinical features and diagnosis of male
hypogonadism".)
● Skin – Men with iron overload syndromes as the cause of infertility may have diffuse or
patchy hyperpigmentation. Men with Cushing's syndrome may have thin skin, ecchymoses,
and/or broad purple striae. Loss of pubic, axillary, and facial hair, decreased oiliness of the
skin, and fine facial wrinkling suggest longstanding testosterone deficiency.
● External genitalia – The genital examination is the most important aspect of physical
examination in the assessment of an infertile man. Several abnormalities that affect fertility
can be recognized by examination of the external genitalia:
• Incomplete sexual development can be recognized by examining the phallus and testes
and finding small testes and other findings of incomplete pubertal development
(Tanner stage less than 5). (See "Normal puberty".)
• Diseases that affect sperm maturation and transport can be detected by examination of
the scrotum for absence of the vasa, epididymal thickening, and large varicoceles. (See
"Nonacute scrotal conditions in adults", section on 'Varicocele' and "Cystic fibrosis:
Clinical manifestations and diagnosis", section on 'Infertility'.)
• Approximately 90 percent of testicular volume consists of seminiferous tubules that

make sperm, and subnormal testicular volumes correlate with decreased sperm
production and sperm concentrations in the ejaculate. Decreased volume of the
seminiferous tubules can be detected by measuring testicular size by Prader

orchidometer or calipers. The Prader orchidometer consists of a series of plastic
ellipsoids with a volume from 1 to 35 cc ( picture 1). In an adult man, a testicular
volume less than 15 cc (as measured by Prader orchidometry) or a testicular length
(measured on the longest axis) less than 3.6 cm is considered small.
Prader orchidometry is adequate for assessment of testicular volumes in the evaluation of the
infertile man [7]. Prader orchidometry has been reported to estimate greater (approximately 25
to 30 percent) testicular volumes than those by ultrasound, and the overestimation in size is
greater with smaller testicles [8-10]. However, these studies showed a high correlation between
volumes measured by Prader orchidometry and ultrasound. A systematic review confirmed that
ultrasound is more accurate than the Prader orchidometer to assess testicular volume, but that
measurements by both methods are closely related.
Semen analysis — Semen analysis is the key laboratory assessment of the male partner of an
infertile couple. The standard semen analysis consists of the following:
● Semen volume and pH

● Microscopy for:
• Sperm concentration, count, motility, and morphology
• Debris and agglutination
• Leukocyte count
• Immature germ cells
The semen sample should be collected after two to seven days of ejaculatory abstinence. If
possible, the patient should collect the sample by masturbation at the doctor's office. If not
possible, then the sample may be collected at home and delivered to the laboratory within an
hour of collection.
The semen analysis should be performed using standardized methods, preferably those
described in the World Health Organization (WHO) Laboratory Manual for the Examination and
Processing of Human Semen [11]. In addition, the laboratory should employ internal quality
control measures and participate in external quality control programs available from national
andrology, clinical chemistry, and pathology societies [11,12]. A single seminal fluid analysis
suffices for the initial evaluation of male infertility, but one to two additional fluid analyses
should be performed if any abnormalities are found [5].
Reference limits — The WHO has published lower reference limits for semen analyses
[13]. The following parameters represent the generally accepted 5th percentile (lower reference
limits and 95% CIs in parentheses), derived from a study of over 1900 men whose partners had a
time to pregnancy of ≤12 months [13]:
● Volume – 1.5 mL (95% CI 1.4-1.7)

● Sperm concentration – 15 million spermatozoa/mL (95% CI 12-16)
● Total sperm number – 39 million spermatozoa per ejaculate (95% CI 33-46)
● Morphology – 4 percent normal forms (95% CI 3-4), using "strict" Tygerberg method [11]
● Vitality – 58 percent live (95% CI 55-63)
● Progressive motility – 32 percent (95% CI 31-34)
● Total (progressive and nonprogressive) motility – 40 percent (95% CI 38-42)
Additional evaluation — After the initial evaluation (history, physical examination, and semen
analysis), men with infertility should undergo the following evaluation:
Men with a normal semen analysis — Male partners in an infertile couple may have
idiopathic male infertility. Other possibilities include infertility of the female partner or a couples'
infertility factor (including insufficient frequency or duration of unprotected vaginal intercourse
that should occur at least one to two times weekly for optimal conception rates). After complete
evaluation of the female partner and treatment of reversible causes of female infertility, the
couple should consider referral to a specialist in ART, such as in vitro fertilization (IVF).
Men with an abnormal semen analysis — Most infertile men with abnormal semen analyses
have abnormalities in sperm concentrations, morphology, and motility.
Normal sperm concentration, abnormal morphology and/or motility — In an infertile

couple with a male partner who has a normal sperm concentration but abnormal sperm
morphology and/or motility, referral to a specialist in ART, such as intracytoplasmic sperm
injection (ICSI), might be useful. (See "Treatments for male infertility", section on 'IVF with ICSI'.)
Sperm concentration <5 million/mL — Because Klinefelter syndrome is common in men

presenting with infertility and sperm concentrations <5 million/mL, serum total testosterone (on
a blood sample obtained between 8 and 10 AM), serum follicle-stimulating hormone (FSH), and
luteinizing hormone (LH) measurements should be performed in these men [5,14]. The results of
the endocrine testing and details from the history and physical examination can help identify the
cause of the infertility.
Severe oligozoospermia or azoospermia — Men with azoospermia or severe

oligozoospermia also need endocrine testing; further evaluation also depends upon the results
(see 'Endocrine testing' below). In addition to undergoing endocrine testing, men with severe
oligozoospermia or azoospermia require genetic testing. (See 'Genetic tests' below.)
Some men may require transrectal ultrasound for evaluation of obstructive azoospermia (those
who have normal endocrine testing, normal testicular volume, palpable vasa deferentia on
examination, and azoospermia). (See 'Scrotal and transrectal ultrasound' below.)
Endocrine testing — The endocrine assessment of an infertile man with a low sperm
concentration (<5 million/mL) includes measurements of serum total testosterone, LH, and FSH
and other tests as clinically indicated [15,16]. Serum total testosterone should be measured on a
blood sample obtained between 8 and 10 AM. The measurement should be repeated in men
with borderline values (see "Clinical features and diagnosis of male hypogonadism", section on
'Serum total testosterone'). The following combinations of serum testosterone, LH, and FSH
suggest the following diagnoses:
● Low testosterone, and high FSH and LH – Primary (hypergonadotropic) hypogonadism

(affecting both spermatogenesis and Leydig cell function). These men should have a
karyotype performed. Some experts do not recommend a karyotype if there is another
clearly identified cause of primary hypogonadism. However, Klinefelter syndrome is
common enough in infertile men with primary hypogonadism that karyotyping is
reasonable even in the man with another cause of primary hypogonadism [14,17]. (See
'Genetic tests' below and "Principles of magnetic resonance imaging".)
● Normal testosterone and LH and high FSH – Primary (hypergonadotropic)

hypogonadism (seminiferous tubule damage without Leydig cell dysfunction). These men
have isolated defects in spermatogenesis and intact sex hormone steroidogenesis with
normal circulating testosterone concentrations. (See "Causes of male infertility", section on
'Primary testicular defects in spermatogenesis'.)
● Low testosterone, but FSH and LH not elevated (normal or low) – Secondary
(hypogonadotropic) hypogonadism. Serum prolactin should be measured in men with a
low serum testosterone concentration, and normal to low serum LH and iron overload
syndromes should be excluded with iron studies. Men with low serum testosterone and low
gonadotropin concentrations should be evaluated for a sellar mass, other causes of
secondary hypogonadism, and other pituitary hormone deficiencies (secondary
hypothyroidism and hypoadrenalism). (See "Clinical features and diagnosis of male
hypogonadism", section on 'Secondary hypogonadism'.)
● High testosterone and LH, but normal FSH – Partial androgen resistance. (See
"Pathogenesis and clinical features of disorders of androgen action".)
● Normal testosterone, LH, and FSH – Further evaluation depends upon findings on semen
analysis (eg, azoospermia, oligozoospermia, asthenozoospermia, or teratozoospermia).
(See "Treatments for male infertility", section on 'Normal serum T, normal LH and FSH'.)
Men with azoospermia and normal endocrine testing should be evaluated for ejaculatory
duct obstruction. (See "Treatments for male infertility", section on 'Obstruction of
epididymis or ejaculatory duct'.)
Most infertile men who have normal serum testosterone concentrations, normal serum
gonadotropin concentrations, and a primary defect in spermatogenesis have sperm in the
ejaculate, but the numbers of sperm with normal motility and/or normal morphology are
low. Clinicians should treat infertile men with oligozoospermia and normal serum
hormones similarly to men with idiopathic infertility (ie, men with normal semen analyses
and normal serum hormones). There is no clearly effective medical therapy for these men.
Strategies include continuation of attempts at natural conception or ART. (See "Treatments
for male infertility", section on 'Assisted reproductive technologies'.)
● Low sperm count and very low LH in a man who is very muscular – Suspicious for
androgen abuse. (See "Use of androgens and other hormones by athletes".)
Scrotal and transrectal ultrasound — Scrotal or testicular ultrasound are useful if a patient
has normal testicular volumes, normal serum testosterone, FSH, and LH, and azoospermia
because the likely diagnosis is obstructive azoospermia. Scrotal or transrectal ultrasound
should be done if the vasa differentia are not palpable on examination; this finding is important
to confirm because it is associated with cystic fibrosis. Congenital absence of the vas deferentia
may be the only manifestation of cystic fibrosis [16]. Ejaculatory duct obstruction can be
diagnosed by a scrotal or transrectal ultrasound showing dilated seminal vesicles [18-21].
Transrectal ultrasound might be modestly more sensitive in detecting obstructive azoospermia
[22]. Patients with obstructive azoospermia should be referred to a urologist specialized in
infertility for further evaluation and treatment. (See "Treatments for male infertility", section on
'Obstructive azoospermia'.)
Although there is some controversy about the clinical significance of nonpalpable varicoceles in
infertile men, it is not necessary to perform scrotal or transrectal ultrasound to detect small
varicoceles because palpation is sufficient to detect large varicoceles that might be associated
with male infertility [5,7,23].
Magnetic resonance imaging — Magnetic resonance imaging might be slightly more sensitive
for detecting partial ejaculatory duct obstruction, but the expense of this imaging modality is
not generally justifiable [20,21].
Genetic tests — Karyotyping and testing for Y chromosome microdeletions should be done in
infertile men with sperm concentrations <5 million/mL before any ART therapy is performed
[5,14]. Klinefelter syndrome is common in these men, and chromosomal translocations occur in
up to 15 percent of men with severe oligozoospermia or azoospermia [5,14,24,25]. Men with
absence of bilateral vasa differentia should be tested for gene mutations associated with cystic
fibrosis (cystic fibrosis transmembrane conductance regulator [CFTR] gene mutations) [5]. ART
has made it possible for men with severe oligozoospermia and azoospermia to pursue fertility,
but there is a small risk of transferring somatic and sex chromosome abnormalities,
microdeletions of the Y chromosome, X chromosome defects, and CFTR gene mutations to the
offspring [5,14,17]. (See "Treatments for male infertility", section on 'Retrieval of sperm'.)
SEMEN ANALYSES
Semen analysis interpretation — Most infertile men with abnormal semen analyses have
abnormalities in sperm concentration, morphology, and motility.
Low volume
● Low semen volume with normal sperm concentration is most likely due to incomplete
collection of the ejaculate or partial retrograde ejaculation. The patient should be asked to
return for a carefully collected repeat semen sample after emptying the bladder; post-
ejaculation urine can be collected to assess whether there is retrograde ejaculation [16].
● Low semen volume and low sperm concentration may also be seen in some men with
testosterone deficiency.
Endocrine assessment of possible testosterone deficiency is reviewed above. (See

'Endocrine testing' above.)
● A low volume with azoospermia (no sperm) or severe oligozoospermia (severely

subnormal sperm concentration) suggests genital tract obstruction (eg, congenital absence
of the vas deferens and seminal vesicles, or ejaculatory duct obstruction). (See 'Scrotal and
transrectal ultrasound' above.)
• Congenital absence of vas deferens is suspected by physical examination and confirmed

by scrotal or transrectal ultrasound.
• Ejaculatory duct obstruction is diagnosed by the finding of dilated seminal vesicles on

scrotal or transrectal ultrasonography. (See 'Scrotal and transrectal ultrasound' above.)
Low concentration — The lower reference limit for sperm concentration is 15 million/mL (95%
CI 12-16) [13] (see 'Reference limits' above). However, some men with sperm counts considered
to be low can be fertile, while others above the lower limit of normal can be subfertile [26-28]. In
addition, for the purposes of in vitro fertilization (IVF), 10 million/mL or even less can be
satisfactory [11].
● Lack of sperm in the ejaculate does not indicate the absence of sperm production; these
patients should be evaluated for retrograde ejaculation, congenital absence of the vas
deferens, and other causes of obstructive azoospermia. (See "Causes of male infertility",
section on 'Sperm transport disorders'.)
● If few or no spermatozoa per high-power field are observed, there are special techniques
to increase the sensitivity of detecting sperm in the ejaculate [13,29]. Identifying even a few
spermatozoa in the ejaculate is useful because it indicates that assisted reproductive
technologies (ART) might be effective. (See "Treatments for male infertility", section on 'IVF
with ICSI'.)
Abnormal morphology — The criteria for sperm morphology are based on length, width,
width ratio, area occupied by the acrosome, and neck and tail defects [13,30,31]. Sperm
morphology assessment has modest clinical value [32]. It is useful for detecting selected, very
rare genetic causes of male infertility [32]. It has been claimed that morphologic assessment has
good predictive value for pregnancy rates after IVF [30,31,33], but these claims are controversial
and not well supported by clinical studies [32].
Round cells in the seminal fluid may be leukocytes, immature germ cells, or degenerating
epithelial cells [11]. Presence of immature germ cells in the semen usually indicates disorders of
spermatogenesis. White blood cells, mainly polymorphonuclear leukocytes, are frequently
present in the seminal fluid. Presence of increased white blood cells in the ejaculate may be a
marker of genital infection/inflammation and may be associated with poor semen quality
because of the release of reactive oxygen species from the leukocytes. The suggested cutoff for
the diagnosis of a possible infection is one million leukocytes/mL of ejaculate. However, this
cutoff has poor predictive value for bacterial infection [34,35].
Poor motility — In general, motility is not an important factor in independently predicting the
probability of natural pregnancy, unless a very high percentage of sperm in ejaculate are
immotile [36]. Men with a very high percentage of immotile sperm might still be treatable with
intracytoplasmic sperm injection (ICSI) [36]. (See "Treatments for male infertility", section on 'IVF
with ICSI'.)
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Prediction of fertility — The standard semen analysis provides descriptive data that do not
always distinguish fertile from infertile men [36]. In one prospective study of 430 couples,
among those with a sperm concentration ≥40 x 106/mL, 65 percent achieved pregnancy
compared with 51 percent of those with lower sperm concentrations [37]. In a study of male
partners in 765 infertile couples in which the female partners had normal infertility workup and
in 696 control fertile couples recruited from prenatal classes, there was extensive overlap
between fertile and infertile men in sperm concentration, motility, and morphology [28].
However, men who have a "triple" defect of low sperm concentrations, low percentage of normal
morphology, and low percentage of motile sperm have a high probability of infertility [36].
At-home test — At-home testing of sperm quality is commercially available. We do not

recommend these at-home tests in the evaluation of male infertility, because these tests do not
assess sperm morphology and they have not been carefully studied for reliability [38,39].
Specialized sperm and semen tests — We suggest not doing specialized sperm and semen
tests, such as antisperm autoantibodies, seminal fluid fructose, or semen culture.
● The presence of agglutination in the initial semen analysis suggests sperm autoantibodies
that are present in 4 to 8 percent of infertile men [11]. However, sperm autoantibodies do
not appear to cause infertility. (See "Causes of male infertility".)
● Sperm biochemistry is frequently described in semen analyses but is rarely useful in clinical
practice. The most commonly ordered test is fructose, which is a marker of seminal vesicle
function, and seminal fructose might be low in men with ejaculatory duct obstruction [40].
This test is not routinely used.
● Semen culture is sometimes performed in men whose semen samples contain

inflammatory cells, but semen culture results have not been proven to be useful.
● There are numerous other specialized sperm and semen tests (including tests of sperm
DNA damage) that are used in some fertility clinics and laboratories, but these tests lack
standardization and evidence to support their routine use [36,41,42]. Tests of sperm DNA
fragmentation might prove to be useful, but the evidence to support their use is based
almost exclusively on retrospective studies, case series, and expert opinion [43].
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Male infertility or
hypogonadism".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Male infertility (The Basics)")
● Beyond the Basics topics (see "Patient education: Treatment of male infertility (Beyond the
Basics)")
SUMMARY AND RECOMMENDATIONS
● Initial evaluation
• Identify treatable causes – The evaluation of male infertility should focus on

identifying treatable causes and factors that might affect the outcome of therapy or the
health of offspring. (See 'Diagnostic approach' above.)
• Female partner – The female partner must be evaluated thoroughly before or

concurrent with the male partner of an infertile couple. (See 'Initial visit' above.)
• Semen analysis – Semen analysis is the fundamental investigation for the infertile male
and directs the subsequent evaluation. (See 'Semen analysis' above.)
If the initial semen analysis has any abnormality, it should be repeated. If repeated
semen analyses demonstrate a sperm concentration less than 5 million
spermatozoa/mL, then serum testosterone, serum follicle-stimulating hormone (FSH),

and luteinizing hormone (LH) should be measured. (See 'Semen analysis' above.)
● Additional evaluation
• Scrotal and transrectal ultrasound – Impalpable vasa deferentia on physical

examination suggest congenital absence of vasa deferentia. This finding should be
confirmed with ultrasound. These patients should be tested for the cystic fibrosis
transmembrane conductance regulator (CFTR) gene mutations, and, if positive in either
the man or the female partner, genetic counseling should be offered before assisted
reproductive technology (ART) therapies are performed.
• Ejaculatory duct obstruction – If seminal fluid pH and volume are low (<1.5 mL) in a
man with azoospermia, normal-sized testes, and normal serum testosterone, FSH, and
LH concentrations, retrograde ejaculation or ejaculatory duct obstruction is likely and a
postejaculatory urine sample analysis and transrectal ultrasound imaging should be
performed. (See 'Scrotal and transrectal ultrasound' above.)
● Genetic testing – Karyotyping and testing for Y chromosome microdeletions should be

offered to all infertile men with sperm concentrations <5 million/mL before any ART
therapy is performed. (See 'Genetic tests' above.)
ACKNOWLEDGMENTS
The UpToDate editorial staff acknowledges Ronald Swerdloff, MD, and Christina Wang, MD, who
contributed to an earlier version of this topic review.
Use of UpToDate is subject to the Terms of Use.
REFERENCES
1. Practice Committee of tAmerican Society for Reproductive Medicine. Definitions of infertility

and recurrent pregnancy loss. Fertil Steril 2008; 90:S60.
2. Evers JL. Female subfertility. Lancet 2002; 360:151.
3. Annual Capri Workshop Group. Towards a more pragmatic and wiser approach to infertility
care. Hum Reprod 2019; 34:1165.
4. Winters BR, Walsh TJ. The epidemiology of male infertility. Urol Clin North Am 2014; 41:195.
5. Barratt CLR, Björndahl L, De Jonge CJ, et al. The diagnosis of male infertility: an analysis of
the evidence to support the development of global WHO guidance-challenges and future
research opportunities. Hum Reprod Update 2017; 23:660.
6. Kruger TF, Acosta AA, Simmons KF, et al. Predictive value of abnormal sperm morphology in
in vitro fertilization. Fertil Steril 1988; 49:112.
7. Lotti F, Maggi M. Ultrasound of the male genital tract in relation to male reproductive
health. Hum Reprod Update 2015; 21:56.
8. Sakamoto H, Saito K, Oohta M, et al. Testicular volume measurement: comparison of

ultrasonography, orchidometry, and water displacement. Urology 2007; 69:152.
9. Diamond DA, Paltiel HJ, DiCanzio J, et al. Comparative assessment of pediatric testicular
volume: orchidometer versus ultrasound. J Urol 2000; 164:1111.
10. Mbaeri TU, Orakwe JC, Nwofor AM, et al. Accuracy of Prader orchidometer in measuring
testicular volume. Niger J Clin Pract 2013; 16:348.
11. World Health Organization Department of Reproductive Health and Research. World Health
Organization Laboratory Manual for the Examination and Processing of Human Semen, 5th
ed, World Health Organization, Geneva, Switzerland 2010.
12. McLachlan RI, Baker HW, Clarke GN, et al. Semen analysis: its place in modern reproductive
medical practice. Pathology 2003; 35:25.
13. Cooper TG, Noonan E, von Eckardstein S, et al. World Health Organization reference values
for human semen characteristics. Hum Reprod Update 2010; 16:231.
14. McLachlan RI. Approach to the patient with oligozoospermia. J Clin Endocrinol Metab 2013;
98:873.
15. Sokol RZ. Endocrinology of male infertility: evaluation and treatment. Semin Reprod Med
2009; 27:149.
16. Anawalt BD. Approach to male infertility and induction of spermatogenesis. J Clin Endocrinol
Metab 2013; 98:3532.
17. Hofherr SE, Wiktor AE, Kipp BR, et al. Clinical diagnostic testing for the cytogenetic and
molecular causes of male infertility: the Mayo Clinic experience. J Assist Reprod Genet 2011;
28:1091.
18. Meacham RB, Hellerstein DK, Lipshultz LI. Evaluation and treatment of ejaculatory duct
obstruction in the infertile male. Fertil Steril 1993; 59:393.
19. Jarow JP. Transrectal ultrasonography in the diagnosis and management of ejaculatory duct
obstruction. J Androl 1996; 17:467.
20. Jurewicz M, Gilbert BR. Imaging and angiography in male factor infertility. Fertil Steril 2016;
105:1432.
21. Huang IS, Wren J, Bennett NE, Brannigan RE. Clinical Consultation Guide on Imaging in Male
Infertility and Sexual dysfunction. Eur Urol Focus 2018; 4:338.
22. Abdulwahed SR, Mohamed EE, Taha EA, et al. Sensitivity and specificity of ultrasonography
in predicting etiology of azoospermia. Urology 2013; 81:967.
23. Kroese AC, de Lange NM, Collins J, Evers JL. Surgery or embolization for varicoceles in
subfertile men. Cochrane Database Syst Rev 2012; 10:CD000479.
24. McLachlan RI, O'Bryan MK. Clinical Review#: State of the art for genetic testing of infertile
men. J Clin Endocrinol Metab 2010; 95:1013.
25. Martin RH. Cytogenetic determinants of male fertility. Hum Reprod Update 2008; 14:379.
26. Jørgensen N, Andersen AG, Eustache F, et al. Regional differences in semen quality in
Europe. Hum Reprod 2001; 16:1012.
27. Swan SH, Brazil C, Drobnis EZ, et al. Geographic differences in semen quality of fertile U.S.
males. Environ Health Perspect 2003; 111:414.
28. Guzick DS, Overstreet JW, Factor-Litvak P, et al. Sperm morphology, motility, and
concentration in fertile and infertile men. N Engl J Med 2001; 345:1388.
29. Cooper TG, Hellenkemper B, Jonckheere J, et al. Azoospermia: virtual reality or possible to
quantify? J Androl 2006; 27:483.
30. Menkveld R, Stander FS, Kotze TJ, et al. The evaluation of morphological characteristics of
human spermatozoa according to stricter criteria. Hum Reprod 1990; 5:586.
31. Kruger TF, du Toit TC, Franken DR, et al. Sperm morphology: assessing the agreement
between the manual method (strict criteria) and the sperm morphology analyzer IVOS.
Fertil Steril 1995; 63:134.
32. Gatimel N, Moreau J, Parinaud J, Léandri RD. Sperm morphology: assessment,

pathophysiology, clinical relevance, and state of the art in 2017. Andrology 2017; 5:845.
33. Kruger TF, Menkveld R, Stander FS, et al. Sperm morphologic features as a prognostic factor
in in vitro fertilization. Fertil Steril 1986; 46:1118.
34. Wolff H. The biologic significance of white blood cells in semen. Fertil Steril 1995; 63:1143.
35. Lackner J, Schatzl G, Horvath S, et al. Value of counting white blood cells (WBC) in semen
samples to predict the presence of bacteria. Eur Urol 2006; 49:148.
36. Wang C, Swerdloff RS. Limitations of semen analysis as a test of male fertility and
anticipated needs from newer tests. Fertil Steril 2014; 102:1502.
37. Bonde JP, Ernst E, Jensen TK, et al. Relation between semen quality and fertility: a
population-based study of 430 first-pregnancy planners. Lancet 1998; 352:1172.
38. Björndahl L, Kirkman-Brown J, Hart G, et al. Development of a novel home sperm test. Hum
Reprod 2006; 21:145.
39. Klotz KL, Coppola MA, Labrecque M, et al. Clinical and consumer trial performance of a
sensitive immunodiagnostic home test that qualitatively detects low concentrations of
sperm following vasectomy. J Urol 2008; 180:2569.
40. Dieudonné O, Godin PA, Van-Langendonckt A, et al. Biochemical analysis of the sperm and
infertility. Clin Chem Lab Med 2001; 39:455.
41. Zini A, Bach PV, Al-Malki AH, Schlegel PN. Use of testicular sperm for ICSI in oligozoospermic
couples: how far should we go? Hum Reprod 2017; 32:7.
42. Tomlinson M, Lewis S, Morroll D, British Fertility Society. Sperm quality and its relationship
to natural and assisted conception: British Fertility Society guidelines for practice. Hum
Fertil (Camb) 2013; 16:175.
43. Dutta S, Henkel R, Agarwal A. Comparative analysis of tests used to assess sperm chromatin
integrity and DNA fragmentation. Andrologia 2021; 53:e13718.
Topic 7453 Version 21.0
GRAPHICS
Causes of male infertility
Endocrine and systemic disorders (hypogonadotropic hypogonadism)
Congenital disorders
Congenital GnRH deficiency (Kallmann syndrome)

Iron overload syndromes
Multiorgan genetic disorders (Prader-Willi syndrome, Laurence-Moon-Biedl syndrome,
familial cerebellar ataxia)
Acquired disorders
Pituitary and hypothalamic tumors (pituitary macroadenoma, craniopharyngioma)

Pituitary and hypothalamic infiltrative disorders (sarcoidosis, histiocytosis, tuberculosis,
fungal infections)
Pituitary and hypothalamic lymphocytic infundibulitis or hypophysitis
Head trauma, intracranial radiation, or surgery
Vascular (pituitary infarction, aneurysm)
Hormonal (hyperprolactinemia, androgen excess, estrogen excess, cortisol excess)
Drugs (exogenous androgens, opioids and psychotropic drugs, GnRH agonists or
antagonists)
Systemic disorders
Severe systemic illness

Nutritional deficiencies
Morbid obesity
Primary testicular defects in spermatogenesis
Congenital disorders
Klinefelter syndrome (XXY) and its variants (XXY/XY, XXXY)

Cryptorchidism
Myotonic dystrophy
Functional prepubertal castrate syndrome (congenital anorchia)
Androgen insensitivity syndromes
5-alpha-reductase deficiency
Estrogen receptor or synthesis disorders
Acquired disorders
Varicocele (large, palpable without Valsalva maneuver)
Infections – Viral orchitis (mumps, echovirus, arbovirus), granulomatous orchitis (leprosy,

tuberculosis), epididymo-orchitis (gonorrhea, chlamydia)
Drugs – Alkylating agents, alcohol, marijuana, antiandrogens, ketoconazole, spironolactone,
histamine-2 receptor antagonists, ionizing radiation
Environmental toxins – Dibromochloropropane, carbon disulfide, cadmium, lead, mercury,
environmental estrogens, and phytoestrogens; smoking; hyperthermia
Immunologic disorders, including polyglandular autoimmune disease and antisperm
antibodies
Trauma
Testicular torsion
Systemic illness
Idiopathic dysspermatogenesis
Renal failure, hepatic cirrhosis, cancer, sickle cell disease, amyloidosis, vasculitis, celiac
disease
Genetic causes of dysspermatogenesis
Y-chromosome microdeletions and related disorders

Autosomal and X-chromosome defects
Mutations causing severe defects in sperm morphology
Sperm transport disorders
Epididymal dysfunction (drugs, infection)

Abnormalities of the vas deferens (congenital absence, Young syndrome, infection, vasectomy)
Seminal vesicles and prostate
Ejaculatory ducts disorders
Sexual dysfunction
Infrequent vaginal intercourse, erectile dysfunction, and premature ejaculation
Idiopathic male infertility
GnRH: gonadotropin-releasing hormone.
Graphic 54356 Version 5.0
Prader orchidometer
Photo of a Prader orchidometer for measuring testicular size. On physical examination, the patient's testicula
volume is estimated by palpation and comparison with the models on the orchidometer. Each of the beads is
labeled with its volume, ranging from 1 to 25 mL. Prepubertal sizes are 1 to 3 mL, pubertal sizes are 4 to 12 m
and adult sizes are 12 to 25 mL.
Graphic 117431 Version 1.0
Contributor Disclosures
Bradley D Anawalt, MD No relevant financial relationship(s) with ineligible companies to
disclose. Stephanie T Page, MD, PhD No relevant financial relationship(s) with ineligible companies to
disclose. Peter J Snyder, MD Grant/Research/Clinical Trial Support: AbbVie [Hypogonadism]; Crinetics
[Acromegaly]; Novartis [Cushing's]; Recordati [Cushing's]. Consultant/Advisory Boards: AbbVie
[Hypogonadism]; Novartis [Cushing's]; Pfizer [Acromegaly]; Teva Pharmaceuticals [Cushing's]. All of the
relevant financial relationships listed have been mitigated. Alvin M Matsumoto, MD Consultant/Advisory
Boards: AbbVie [Testosterone]; Partnership for Clean Competition [Anabolic steroid doping and testing]; US
Anti-Doping Agency [Board of Directors, performance enhancing drug doping and testing]. All of the
relevant financial relationships listed have been mitigated. Kathryn A Martin, MD No relevant financial
relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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18/5/23, 18:43 Approach to the male with infertility - UpToDate

Official reprint from UpToDate®

Literature review current through: Apr 2023.

CATEGORIES OF MALE INFERTILITY

● Endocrine and systemic disorders with hypogonadotropic hypogonadism – 5 to 15

● Primary testicular defects in spermatogenesis – 70 to 80 percent. Klinefelter syndrome

● Sperm transport disorders – 2 to 5 percent.

● Idiopathic male infertility – 10 to 20 percent. Idiopathic male infertility should be

● Sexual developmental history, including testicular descent, pubertal development, loss of

● Infections, such as mumps orchitis, sinopulmonary symptoms, sexually transmitted

steroids, corticosteroids, cytotoxic chemotherapy (current or past), drugs that cause

• Approximately 90 percent of testicular volume consists of seminiferous tubules that

seminiferous tubules can be detected by measuring testicular size by Prader

● Semen volume and pH

● Volume – 1.5 mL (95% CI 1.4-1.7)

Normal sperm concentration, abnormal morphology and/or motility — In an infertile

Sperm concentration <5 million/mL — Because Klinefelter syndrome is common in men

Severe oligozoospermia or azoospermia — Men with azoospermia or severe

● Low testosterone, and high FSH and LH – Primary (hypergonadotropic) hypogonadism

● Normal testosterone and LH and high FSH – Primary (hypergonadotropic)

Endocrine assessment of possible testosterone deficiency is reviewed above. (See

● A low volume with azoospermia (no sperm) or severe oligozoospermia (severely

• Congenital absence of vas deferens is suspected by physical examination and confirmed

• Ejaculatory duct obstruction is diagnosed by the finding of dilated seminal vesicles on

At-home test — At-home testing of sperm quality is commercially available. We do not

● Semen culture is sometimes performed in men whose semen samples contain

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Basics topics (see "Patient education: Male infertility (The Basics)")

SUMMARY AND RECOMMENDATIONS

• Identify treatable causes – The evaluation of male infertility should focus on

• Female partner – The female partner must be evaluated thoroughly before or

spermatozoa/mL, then serum testosterone, serum follicle-stimulating hormone (FSH),

• Scrotal and transrectal ultrasound – Impalpable vasa deferentia on physical

● Genetic testing – Karyotyping and testing for Y chromosome microdeletions should be

Use of UpToDate is subject to the Terms of Use.

1. Practice Committee of tAmerican Society for Reproductive Medicine. Definitions of infertility

2. Evers JL. Female subfertility. Lancet 2002; 360:151.

8. Sakamoto H, Saito K, Oohta M, et al. Testicular volume measurement: comparison of

32. Gatimel N, Moreau J, Parinaud J, Léandri RD. Sperm morphology: assessment,

Causes of male infertility

Endocrine and systemic disorders (hypogonadotropic hypogonadism)

Congenital GnRH deficiency (Kallmann syndrome)

Pituitary and hypothalamic tumors (pituitary macroadenoma, craniopharyngioma)

Severe systemic illness

Primary testicular defects in spermatogenesis

Klinefelter syndrome (XXY) and its variants (XXY/XY, XXXY)

Varicocele (large, palpable without Valsalva maneuver)

Infections – Viral orchitis (mumps, echovirus, arbovirus), granulomatous orchitis (leprosy,

Genetic causes of dysspermatogenesis

Y-chromosome microdeletions and related disorders

Sperm transport disorders

Epididymal dysfunction (drugs, infection)

Infrequent vaginal intercourse, erectile dysfunction, and premature ejaculation

Idiopathic male infertility

GnRH: gonadotropin-releasing hormone.

Graphic 54356 Version 5.0