Evaluation of infertile male

Are males going to become extinct?

Contents of discussion
I. When one should evaluate a male in fertility work-ups?
II. What is the Overall contribution of male in infertility?
III. What things should be kept in mind while going for Basic
evaluation ( reproductive history and semen analysis ) ?
IV. What is the relevance of Advanced evaluation: endocrines,
ultrasonography ,specialized tests and DNA Fragmentation tests
V. Role of Genetic screening of infertile males?

Lets revise the old basics of fertility evaluation

 Involve both partners (not the female only)
 Provide information
Chances of conception (theirs and realistic)
Frequency and timing of sexual intercourse(say no to
ovulation kits/temp charting etc)
 Psychological effects of fertility problems & counseling
 Peer pressure/social family pressure (make things worse)
NICE , 2011

In most cases, there are NO obvious signs of an infertility problem.
Intercourse, erections and ejaculation will usually happen without
difficulty. The quantity and appearance of the ejaculated semen
generally appears normal to the naked eye

Evaluation for infertility is indicated for couples who fail to achieve a
successful pregnancy after 12 months or more of regular unprotected
intercourse
Earlier evaluation and treatment may be justified, based on medical
history and physical findings and is warranted after 6 months for
couples in which the female partner is over age 35 years
ASRM , 2008

Earlier evaluation and treatment in males:
Problems with sexual function — for example, difficulty with
erection, penetration or ejaculation
Pain, swelling or a lump in the testicle area
Recurrent respiratory infections
Decreased facial or body hair or other signs of a chromosomal or
hormonal abnormality
Have had groin, testicle, penis or scrotum surgery
(cryptochidism)
Any history of radiation or chemotherapy or trauma

Relative prevalence of the etiologies of
infertility(%)
Male factor 25-40%
Both male and female factors 10%
Female factor 40-50%
Unexplained infertility 10%
Novak's Gynecology ,14 Ed.
A male factor is solely responsible in approximately 20% of infertile
couples and contributes in another 30% to 40% of couples
Thonneau P, et al., 1991

Nieschlag E, Behre HM (eds), 1997

At a minimum, the initial screening evaluation of the male partner of
an infertile couple should include a reproductive history and analysis
of at least one semen sample. If the initial evaluation is abnormal,
then complete evaluation of the male partner is recommended
ASRM , 2008

CAUSE EVIDENCE
Male age Ford WC et al, 2000
Baird DT et al, 2005
Eskenazi et al,2003
ASRM , 2008
RCOG, 2011
occupational exposures
heat, X-rays, heavy metals (lead, mercury), glycol ethers
and pesticides; dibromochloropropane (DBCP)
RCOG Press; 2004
Jurewicz J, 2009
Sharpe RM, 2010
Cherry N, 2008
electromagnetic waves
mobile Phones / laptops
Agarwal A,2008
Erogul O, 2006
Wdowiak A, 2007
Environmental estrogens (Phytoestrogens) Toppari J, 1996;
Testicular hyperthermia
(wearing loose-fitting underwear /sedentary lifestyle)
Tiemessen CH,1996
Munkelwitz R,1998
RCOG Press; 2004
Magnusdottir EV,2005

EVIDENCE CAUSE
Obesity
(by imbalance of reproductive hormone levels, reduced
SHBG and elevated estrogen levels. Sedentary lifestyle
factors )
Sharpe RM, 2002
Hammoud AO, 2008
Anabolic-androgenic steroids
(by interfering with HPG axis, loss of libido and erectile
dysfunction secondary to low endogenous testosterone
levels)
Gazvani MR, 1997
Menon DK, 2003
de Souza GL, 2011
Heavy alcohol consumption/Tobacco/ smoking
Cannabis/recreational drugs such as cocaine,
amphetamines and opiates
Buffum J, 1982
Vine MF, 1996
Nudell DM, 2002

•Hypospadias
•Micripenis
•Size/ volume
•Consistancy
•Location
Per rectal
examination
•CBAVD/CUAVD
•Epididymal
cyst/distension/
induration
•Size
•Consistancy
Varicocele
(Grade)

 About 90% of semen volume is made up of secretions from the
accessory organs, mainly the prostate and seminal vesicles, with
minor contributions from the bulbourethral (Cowper’s) glands and
epididymides
Weiske, 1994
 The quality of semen specimens varies depending on how the
ejaculate is produced. Ejaculates produced by masturbation and
collected into containers in a room near the laboratory can be of lower
quality than those recovered from non-spermicidal condoms used
during intercourse at home. This difference may reflect a different
form of sexual Arousal
Zavos & Goodpasture, 1989 ; Pound et al., 2002

 During ejaculation the first semen fractions voided are mainly sperm-rich
prostatic fluids, whereas later fractions are dominated by seminal
vesicular fluid
Björndahl & Kv,2003
 The time since the last sexual activity. In the absence of ejaculation,
spermatozoa accumulate in the epididymides, then overflow into the
urethra and are flushed out in urine
Cooper et al., 1993; De Jonge et al., 2004
 Sperm vitality and chromatin are unaffected by increased length of
abstinence
Tyler et al.,1982; De Jonge et al., 2004

 sperm concentrations in semen from young and old men may be the
same, but total sperm numbers may differ, as both the volume of
seminal fluid and total sperm output decrease with age.
Ng et al., 2004
 It is impossible to characterize a man’s semen quality from evaluation
of a single semen sample. It is helpful to examine two or three
samples to obtain baseline data
Poland et al., 1985; Berman et al., 1996; Carlsen et al., 2004;
Castilla et al., 2006; Keel, 2006.

 This is not a test for fertility but a guide for minimal standards of
adequacy
 Semen parameters that lie within the 95% reference interval do not
guarantee fertility and otherwise
 these are not absolute limits and should always be interpreted in
conjunction with relevant clinical information
 There may be regional differences in semen quality, or differences
between laboratories; laboratories should consider preparing their own
reference ranges.

ENDOCRINES
 Some experts believe that all infertile males merit an endocrine
evaluation, but there is no established consensus of opinion. The
minimum initial hormonal evaluation should include measurement of
serum FSH and total testosterone
 An endocrine evaluation is indicated for men having:
1) abnormal semen parameters(<10 million/mL)
2) impaired sexual function
3) other clinical findings that suggest a specific
endocrinopathy
ASRM, 2012

 When the total testosterone level is low (<300 ng/mL), a more
extensive evaluation is indicated and should include a second
measurement of total testosterone and measurements of serum free
testosterone, luteinizing hormone (LH) and prolactin.
 Testosterone levels undergo diurnal variation; they are highest in the
morning, and therefore random measurements should be interpreted
with caution if the result is borderline
Karavolos S,2013
 Inhibin B levels are significantly lower in infertile men than in fertile
men and correlate better with sperm parameters than FSH levels , But
cost is a factor.
Kumanov P, 2006

FSH LH Ts PROLACTIN
NORMAL
SPERMATOGENESIS
NORMAL NORMAL NORMAL NORMAL
ABNORMAL
SPERMATOGENESIS
HIGH NORMAL NORMAL NORMAL
HYPOGONADOTROPIC
HYPOGONADISM
LOW LOW LOW LOW
COMPLETE TESTICULAR
FAILURE/
HYPERGONADOTROPIC
HYPOGONADISM
HIGH HIGH NORMAL/
LOW
NORMAL
PROLACTIN-SECRETING
PITUITARY TUMOR
NORMAL NORMAL LOW HIGH

ULTRASONOGRAPHY
 ultrasonography is only indicated for a minority of infertile male
patients .It can act as a supplementary tool for confused diagnosis
 most scrotal pathology, including varicoceles, spermatoceles, absent
vasa, epididymal induration, and testicular masses can be identified by
careful physical examination

Can be a useful supplementary tool in:
 testicular tumor is detected on physical examination.
 obstructive azoospermia cases to see dilated seminal vesicles or
ejaculatory ducts and/or midline cystic prostatic structures
 Renal ultrasound scan in CBAVD(30% linkage)
 Inconclusive physical examination of the scrotum
 Spermatic venography : recurring varicocele

GENETIC SCREENING
Prevalence of genetic abnormalities
Category Karyotypic
chromosomal
abnormalities
Y-chromosome
micro deletions
CFTR mutation
Normal
spermatogenesis
< 1% 2% Not Increased
Severely impaired
spermatogenesis
5% 7% Not Increased
NonOb Azoospermia 10-15% 16% Not Increased
Obstructive
Azoospermia
Not Increased Not Increased 80%(CBAVD)
50% (CUAVD)
Van Assche E, et al, 1996;Ravel C, et al, 2006 Pryor JL, et al. 1997

 The prevalence of chromosomal abnormalities( both sex and
autosomal) and Y-chromosome microdeletions are increased in
infertile men and are inversely proportional to sperm count, although
sex chromosomal aneuploidy ( Klinefelter syndrome; 47,XXY) is
more common and accounts for about two-thirds of all chromosomal
abnormalities observed in infertile men.
 Couples wherein the male has a gross Karyotypic abnormality are at
increased risk for miscarriages and for having children with
chromosomal and congenital defects
Ravel C, 2006 ; De Braekeleer,1991; Debiec-Rychter M,1992

 Y-chromosome microdeletions are too small to be detected by
standard karyotyping, but can be identified using polymerase chain
reaction techniques to analyze sequence tagged sites that have been
mapped along the entire length of the Y chromosome
 Y deletion analysis has both a diagnostic and prognostic value for
testicular sperm retrieval
• AZAa: very poor prognosis for sperm retrieval
• AZAb: very poor prognosis for sperm retrieval
• AZAc: sperm retrieval can be tried
Oates RD, 2002; Brandell RA, 1998; Krausz C ,2000

Although a microdeletion of the Y chromosome is not known to be
associated with other health problems (besides infertility in son),
recent reports have come up with other phenotype issues like SHOX
gene abnormalities , associated with short stature, mental retardation
and arm and wrist deformities
Jorgez CJ, 2011

 Men with non-obstructive azoospermia or severe oligospermia (<5
million/ mL) are at increased risk for having a definable genetic
abnormality and should be offered karyotype and Y-chromosome
analysis before performing ICSI using their sperm
 Genetic testing for CFTR mutations (to rule out the possibility of
offspring affected with cystic fibrosis) should be offered to the female
partner of men with CBAVD before proceeding with treatments that
use sperm from the affected man.
 Genetic counseling may be offered when a genetic abnormality is
suspected/detected in either the male or female partner
ASRM, 2013

 Evaluation of a patient with a varicocele should include a careful
medical and reproductive history, physical examination and at least
two semen analyses.
 The physical examination should be performed with the patient in
both the recumbent and upright positions.
 Feels like a ‘‘bag of worms’’ which disappears or significantly
reduced in recumbent postion.
 Perform a Valsalva maneuver in a standing position in difficult
situations.

Only larger varicoceles, which are typically easily palpable have been
clearly associated with infertility. Therefore, ancillary diagnostic
measures, such as scrotal ultrasonography, thermography, Doppler
examination, radionuclide scanning, and spermatic venography,
should not be used for the detection of subclinical varicoceles in
patients without a palpable abnormality
ASRM, 2008

INDICATIONS FOR TREATMENT OF A VARICOCELE
When ALL of the following conditions are met:
1) The varicocele is palpable on physical examination of the scrotum(
AND NOT BY USG/DOPPLER)
2) the couple has known infertility
3) the female partner has normal fertility or a potentially treatable
cause of infertility
4) the male partner has abnormal semen parameters

say NO to varicocele repair in:
 Normal semen with clinical palpable varicocele
 Abnormal semen with usg / Doppler showing higher grade
varicocele but clinical non-palpable
 Azoospermia with varicocele??
 Idiopathic semen abnormality
 When otherwise IVF is indicated in couples with the aim being to
improve semen parameters for IVF standards

LEUKO-CYTOSPERMIA
Excessive numbers of leukocytes in the ejaculate (leukocytospermia,
pyospermia) can impair sperm motility and DNA integrity through an
oxidative attack but the damage depends on factors that are impossible
to infer from a semen sample, such as the reason for, timing and
anatomical location of the infitration,as well as the nature of the
leukocytes involved and whether they are in an activated state
Tomlinson et al., 1993; Aitken & Baker, 1995; Rossi & Aitken, 1997

Leukocytes or spermatocytes/tids (Round cells)
 Papanicolaou procedure
 staining coloration
 Nuclear size and shape
 absence of intracellular peroxidase
 leukocyte-specific antigens
 stains specific for the developing acrosome , lectins or specific
antibodies
Couture et al., 1976; Homyk et al., 1990; Ezeh et al., 1998; Johanisson
et al., 2000

IMMUNOLOGICAL INFERTILITY:
 ASAs can form when there is a breach in the blood-testis barrier
(trauma, torsion, biopsy, orchitis, testicular cancer, and vasectomy)
 Sperm-bound antibodies can decrease motility, block penetration of
the cervical mucus and prevent fertilization and decrease the
likelihood for conception
Ayvaliotis B,1985

 Sperm antibodies can be present without sperm agglutination;
equally, agglutination can be caused by factors others than sperm
antibodies.
 The mere presence of sperm antibodies is insufficient for a diagnosis
of sperm autoimmunity. It is necessary to demonstrate that the
antibodies interfere severely with sperm function; done by a sperm–
mucus penetration test

 sperm washing prevents clumping and agglutination, but fertility
rates are similar in patients with or without ASAs
 steroids for both partners has been attempted, with mild improvement
in pregnancy rates and high rates of side effects (60%)
 Routine testing for ASAs can not be recommended, although a high
prevalence is noted in isolated asthenospermia with normal count,
unexplained infertility and semen with high agglutination
Hendry WF, 1990; Francavilla F,1992; Nagy ZP, 1995

DNA fragmentation studies:
 DNA fragmentation’’ refers to denatured or damaged sperm DNA
that cannot be repaired
• single-cell gel electrophoresis assay (Comet)
• terminal deoxynucleotidyl transferase dUTP nick end labeling assay
(TUNEL)
• Sperm Chromatin Structure Assay (SCSA)
 Threshold values used to define an abnormal test are greater than or
equal to 25% to 27% for the SCSA and greater than or equal to 36%
for TUNEL assays
Larson-Cook KL, 2003; Henkel R, 2004

Possible Indications of DNA F studies.
unexplained infertility / arrested embryo development /
poor blastocyst development / multiple failed IVF/ICSI / recurrent
miscarriages / advanced age / varicocoele /
poor semen parameters / exposure to harmful substances
Vanderzwalmen et al., 1991; Ahmadi and Ng ,1999; Twigg et al., 1998;
Larson et al., 2000; Tomlinson et al., 2001

 Although no treatment for abnormal DNA integrity has proven of
clinical value, varicocele repair and antioxidant use may affect sperm
DNA integrity.
 Sperm retrieved from the testis tend to have better sperm DNA quality
in men with abnormal ejaculated sperm DNA integrity.
 The routine use of DNA integrity tests in the clinical evaluation of
male factor infertility is controversial
Collins JA, 2008 ; ASRM, 2008

SUMMARY
 Semen analysis should be done by standards laid down by WHO,2010
 Basic evaluation involves detailed reproductive history and semen
analysis done at least once.
 Repeat if abnormal and go for endocrines and physical examination
(must)
 Routine use of ultrasonography is not justified but can act as a
supplementary tool

SUMMARY
 Genetic testing ( Karyotype and Y-Chromosome Microdeletions)
followed by counseling should be offered to every NOA and men with
severe oligospermia(<5 M/Ml)
 CFTR mutation should be offered to obstructive azoospermia cases of
CBAVD/CBAUD patients.
 Routine use of following should be discouraged till further RCTs:
ASA / DFI / ROS /ACROSOME tests/ Accessory gland functions
( Zinc, Fructose or a-Glucosidase )

Evaluation of infertile male

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