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Created page with " ==== '''INFERTILITY: DIAGNOSIS & EVALUATION''' ==== '''See 2015 CUA Azoospermia Guideline Notes''' ===== '''Diagnosis and Evaluation''' ===== * '''General principles''' ** '''Goals of evaluation are to identify (5):§''' **# '''Potentially correctable conditions for treatment to allow for conception through intercourse or through techniques, such as IUI or IVF, when those approaches would otherwise not be possible''' **# '''Irreversible conditions that are amenable to..."
 
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==== '''INFERTILITY: DIAGNOSIS & EVALUATION''' ====
'''See [https://pubmed.ncbi.nlm.nih.gov/33295257/ 2020 AUA/ASRM Guidelines on Infertility]'''
 
'''See 2015 CUA Azoospermia Guideline Notes'''
'''See 2015 CUA Azoospermia Guideline Notes'''


===== '''Diagnosis and Evaluation''' =====
== General principles ==
* '''Goals of evaluation are to identify (5):§'''
*# '''Potentially correctable conditions for treatment to allow for conception through intercourse or through techniques, such as IUI or IVF, when those approaches would otherwise not be possible'''
*# '''Irreversible conditions that are amenable to ART using the sperm of the male partner'''
*# '''irreversible conditions that are not amenable to the above, and for which donor insemination or adoption are possible options'''
*# '''Life- or health-threatening conditions that may underlie the infertility or associated medical comorbidities that require medical attention'''
*#* '''Male infertility may occasionally be the presenting manifestation of an underlying life-threatening condition such as testicular cancer or pituitary tumours'''
*# '''Genetic abnormalities or lifestyle and age factors that may affect the health of the male patient or of offspring particularly if ART are to be employed'''
* '''For initial infertility evaluation, both male and female partners should undergo concurrent assessment.'''
** Many couples have more than one fertility issue present.
*** For the female partner, tests are indicated to evaluate ovarian reserve, ovulatory function, tubal structures as well as assessment of the uterine cavity.
*** For the male partner, good clinical practice to obtain a reproductive history, perform a physical examination and basic diagnostic tests of reproductive function (Appendix I).
* '''In couples with failed assisted reproductive technology cycles or recurrent pregnancy losses (RPL) (two or more losses), evaluation of the male should be considered.'''
* '''Timing'''
** '''Infertility should be evaluated after 6 months of attempted conception when the female partner is over 35 years of age'''
 
== UrologySchool.com Summary ==
* '''History and physical exam'''
* '''Labs'''
** '''Semen analysis'''
*** '''At least two SAs obtained a month apart are important to consider, especially if the first SA has abnormalparameters.§'''
 
== History and physical exam ==


* '''General principles'''
=== History ===
** '''Goals of evaluation are to identify (5):§'''
* Evaluation of men with secondary infertility should include a focus on conditions or exposures that have developed or occurred after initiation of the earlier pregnancy(ies).'''§'''
**# '''Potentially correctable conditions for treatment to allow for conception through intercourse or through techniques, such as IUI or IVF, when those approaches would otherwise not be possible'''
* '''Risk factors'''
**# '''Irreversible conditions that are amenable to ART using the sperm of the male partner'''
** '''Can be categorized into (TICS - see Infertility: Epidemiology and Etiology Chapter Notes):'''
**# '''irreversible conditions that are not amenable to the above, and for which donor insemination or adoption are possible options'''
**# '''Toxins''' (medications, chemotherapy, radiation, social habits)
**# '''Life- or health-threatening conditions that may underlie the infertility or associated medical comorbidities that require medical attention'''
**# '''Infections''' of the GU tract
**#* '''Male infertility may occasionally be the presenting manifestation of an underlying life-threatening condition such as testicular cancer or pituitary tumours'''
**# '''Childhood''' (congenital causes (recall '''DUNKY-XX'''), hydrocele or hernia surgery, trosion, cryptorchidism)
**# '''Genetic abnormalities or lifestyle and age factors that may affect the health of the male patient or of offspring particularly if ART are to be employed'''
**# '''Sexual history''' (lubricants)
** '''For initial infertility evaluation, both male and female partners should undergo concurrent assessment.'''
* '''Infertility history'''
*** Many couples have more than one fertility issue present.
** Duration of infertility
**** For the female partner, tests are indicated to evaluate ovarian reserve, ovulatory function, tubal structures as well as assessment of the uterine cavity.
** Whether the infertility is primary or secondary
**** For the male partner, good clinical practice to obtain a reproductive history, perform a physical examination and basic diagnostic tests of reproductive function (Appendix I).
** Any treatments to date
** '''In couples with failed assisted reproductive technology cycles or recurrent pregnancy losses (RPL) (two or more losses), evaluation of the male should be considered.'''
** Libido, sexual function, sexual activity
** '''Timing'''
* '''General health of the male''' (diabetes, respiratory issues, recent illnesses)
*** '''Infertility should be evaluated after 6 months of attempted conception when the female partner is over 35 years of age'''
** Medical comorbidities (e.g., hypertension, hyperlipidemia, obesity, diabetes) that can contribute to infertility.
* '''UrologySchool.com Summary'''
** '''If there has been a recent serious medical illness or injury or evidence of a recent reproductive tract infection, semen testing should be repeated at least 3 months following recovery from the illness'''
** '''History and physical exam'''
* '''Surgery of the reproductive tract''': testis cancer, undescended testis, hydrocelectomies, spermatocelectomies, varicocelectomies, vasectomies
** '''Labs'''
** Vasectomy reversal may represent a more cost-effective option compared to IVF in couples with adequate ovarian function'''§'''
*** '''Semen analysis'''
* '''Proven or suspected GU infections/inflammation:''' sexually transmitted infections, epididymo-orchitis, mumps orchitis
**** '''At least two SAs obtained a month apart are important to consider, especially if the first SA has abnormalparameters.§'''
* '''Medications and therapies which might have an adverse impact on spermatogenesis'''
** '''See Infertility: Epidemiology and Etiology Chapter Notes'''
** '''If there has been exposure to any gonadotoxic agents, these medications should be stopped and semen should be retested in 3-6 months'''
* '''Environmental exposures''' (pesticides, excessive heat on the testicles)
* '''Lifestyle''' (cigarette smoking, recreational drugs, alcohol use, stress, anabolic steroid usel)
* '''History of any genetic abnormalities in the patient or the family'''


* '''History and physical exam'''
=== Physical exam ===
** '''History'''
* '''Body habitus'''
*** Evaluation of men with secondary infertility should include a focus on conditions or exposures that have developed or occurred after initiation of the earlier pregnancy(ies).'''§'''
** '''Obese men have'''
*** '''Risk factors'''
*** '''Elevated estradiol'''
**** '''Can be categorized into (TICS - see Infertility: Epidemiology and Etiology Chapter Notes):'''
**** Mechanism: adipose cells have aromatase which metabolizes testosterone to estradiol
****# '''Toxins''' (medications, chemotherapy, radiation, social habits)
*** '''Reduced serum testosterone and reduced SHBG''' (therefore, more bioavailable testosterone component of total testosterone)
****# '''Infections''' of the GU tract
* '''State of virilisation'''
****# '''Childhood''' (congenital causes (recall '''DUNKY-XX'''), hydrocele or hernia surgery, trosion, cryptorchidism)
* '''Abdominal examination'''
****# '''Sexual history''' (lubricants)
** Scars indicative of previous inguinal surgery or treatment of undescended testis
*** '''Infertility history'''
* '''Scrotal examination'''
**** Duration of infertility
** '''Size and consistency of the testis; size correlates well with sperm production'''
**** Whether the infertility is primary or secondary
*** '''Long axis length <4.6cm associated with impaired spermatogenesis'''
**** Any treatments to date
*** '''Volume <20mL considered low'''
**** Libido, sexual function, sexual activity
** Epididymis (engorgement may suggest obstruction)
*** '''General health of the male''' (diabetes, respiratory issues, recent illnesses)
* '''Phallus''' (meatal displacement)
**** Medical comorbidities (e.g., hypertension, hyperlipidemia, obesity, diabetes) that can contribute to infertility.
* '''Prostate and seminal vesicles'''
**** '''If there has been a recent serious medical illness or injury or evidence of a recent reproductive tract infection, semen testing should be repeated at least 3 months following recovery from the illness'''
* '''Vas deferens'''
*** '''Surgery of the reproductive tract''': testis cancer, undescended testis, hydrocelectomies, spermatocelectomies, varicocelectomies, vasectomies
** '''Unilateral absence'''
**** Vasectomy reversal may represent a more cost-effective option compared to IVF in couples with adequate ovarian function'''§'''
*** '''Suggests complete lack of Wolffian (duct development on that side, including renal agenesis.'''
*** '''Proven or suspected GU infections/inflammation:''' sexually transmitted infections, epididymo-orchitis, mumps orchitis
**** '''The absent vas should raise a red flag for possible ipsilateral renal agenesis because the ureteral bud and vas are both derived from the wolffian duct'''
*** '''Medications and therapies which might have an adverse impact on spermatogenesis'''
**** '''Recall, male structures derived from Wolffian ducts:'''
**** '''See Infertility: Epidemiology and Etiology Chapter Notes'''
***** '''Body and tail of epididymis (note efferent ductules and head of epididymis from mesonephric tubules)'''
**** '''If there has been exposure to any gonadotoxic agents, these medications should be stopped and semen should be retested in 3-6 months'''
***** '''Vas deferens'''
*** '''Environmental exposures''' (pesticides, excessive heat on the testicles)
***** '''Seminal vesicles'''
*** '''Lifestyle''' (cigarette smoking, recreational drugs, alcohol use, stress, anabolic steroid usel)
****** Distally, the wolffian ducts join the urogenital sinus by about 30 days gestation, where they develop into the seminal vesicles
*** '''History of any genetic abnormalities in the patient or the family'''
***** '''Ejaculatory duct'''
* '''Physical exam'''
***** '''Appendix epididymis'''
** '''Body habitus'''
**** '''Male structures derived from Müllerian duct (2):'''
*** '''Obese men have'''
****# '''Appendix testis'''
**** '''Elevated estradiol'''
****# '''Prostatic utricle'''
***** Mechanism: adipose cells have aromatase which metabolizes testosterone to estradiol
**** '''Male structures derived from urogenital sinus:'''
**** '''Reduced serum testosterone and reduced SHBG''' (therefore, more bioavailable testosterone component of total testosterone)
****# '''Prostate'''
** '''State of virilisation'''
****# '''Bulbourethral glands'''
** '''Abdominal examination'''
** '''Bilateral absence'''
*** Scars indicative of previous inguinal surgery or treatment of undescended testis
*** '''Consider investigation for CF gene mutation'''
** '''Scrotal examination'''
**** Congenital bilateral absence of the vas deferens (CBAVD) is associated with CF gene mutations in 85% of patients.
*** '''Size and consistency of the testis; size correlates well with sperm production'''
***** The most common CFTR mutation is ΔF508, which is severe
**** '''Long axis length <4.6cm associated with impaired spermatogenesis'''
***** ≈7% of brothers of patients with CBAVD will have also vasal agenesis
**** '''Volume <20mL considered low'''
***** No association between CBAVD and Y microdeletions.
*** Epididymis (engorgement may suggest obstruction)
**** '''If the male partner is being tested for CFTR, such is in CBAVD, both patient and female partner should be tested for CFTR to determine risk of cystic fibrosis in offspring (CUA Azoospermia Guidelines).'''
** '''Phallus''' (meatal displacement)
***** '''Only a portion of CFTR mutations are detected by routine testing.'''
** '''Prostate and seminal vesicles'''
****** '''A male with CBAVD should be assumted to be a CFTR carrier despite a negative CFTR gene test and the female partner still needs to be tested prior to any assisted reproductive techniques.'''
** '''Vas deferens'''
*** '''Semen is almost always of low volume and acidic in patients with CBAVD due to hypoplasia or absence of the seminal vesicles, which provide alkalinity'''
*** '''Unilateral absence'''
** '''In men with congenital bilateral or unilateral absence of the vas deferens who are not carriers of cystic fibrosis mutations, abdominal US to assess for renal agenesis is indicated since these men have a higher chance of having absence of one of their kidneys'''
**** '''Suggests complete lack of Wolffian (duct development on that side, including renal agenesis.'''
*** '''26% of males with unilateral congenital absence of the vas deferens and 11% of males with CBAVD had an absent ipsilateral kidney''';
***** '''The absent vas should raise a red flag for possible ipsilateral renal agenesis because the ureteral bud and vas are both derived from the wolffian duct'''
**** Most of the bilateral CAVD patients with an absent ipsilateral kidney are in patients with no identifiable CF gene mutation.
***** '''Recall, male structures derived from Wolffian ducts:'''
* '''Varicoceles'''
****** '''Body and tail of epididymis (note efferent ductules and head of epididymis from mesonephric tubules)'''
** Large varicoceles are associated with greater preoperative impairment in semen quality than are small varicoceles
****** '''Vas deferens'''
** Varicocele treatment may be more cost effective than assisted-reproductive therapy or can lower the intensity of treatment'''§'''
****** '''Seminal vesicles'''
** '''See Varicocelectomy Chapter Notes'''
******* Distally, the wolffian ducts join the urogenital sinus by about 30 days gestation, where they develop into the seminal vesicles
 
****** '''Ejaculatory duct'''
== Laboratory ==
****** '''Appendix epididymis'''
* '''Serum'''
***** '''Male structures derived from Müllerian duct (2):'''
** '''Initial screen (6):'''
*****# '''Appendix testis'''
**# '''Total testosterone'''
*****# '''Prostatic utricle'''
**# '''SHBG'''
***** '''Male structures derived from urogenital sinus:'''
**# '''Albumin (to calculate bioavailable testosterone)'''
*****# '''Prostate'''
**# '''LH'''
*****# '''Bulbourethral glands'''
**# '''FSH'''
*** '''Bilateral absence'''
**# '''Estradiol'''
**** '''Consider investigation for CF gene mutation'''
*** '''Prolactin, if clinically indicated.'''
***** Congenital bilateral absence of the vas deferens (CBAVD) is associated with CF gene mutations in 85% of patients.
**** '''Total testosterone'''
****** The most common CFTR mutation is ΔF508, which is severe
***** '''≥300 ng/dL considered adequate (164 ng/dL bioavailable)'''
****** ≈7% of brothers of patients with CBAVD will have also vasal agenesis
**** '''LH'''
****** No association between CBAVD and Y microdeletions.
***** '''Determine if hypoandrogenism testicular (primary) or pituitary (secondary) in nature'''
***** '''If the male partner is being tested for CFTR, such is in CBAVD, both patient and female partner should be tested for CFTR to determine risk of cystic fibrosis in offspring (CUA Azoospermia Guidelines).'''
**** '''FSH'''
****** '''Only a portion of CFTR mutations are detected by routine testing.'''
***** '''Indirect assessment of germ cell mass'''
******* '''A male with CBAVD should be assumted to be a CFTR carrier despite a negative CFTR gene test and the female partner still needs to be tested prior to any assisted reproductive techniques.'''
****** '''If normal testicle size and FSH <7.6 IU/L --> consider obstructive azoospermia'''
**** '''Semen is almost always of low volume and acidic in patients with CBAVD due to hypoplasia or absence of the seminal vesicles, which provide alkalinity'''
****** '''If reduced testicle size and FSH >7.6 IU/L --> consider spermatogenic dysfunction'''
*** '''In men with congenital bilateral or unilateral absence of the vas deferens who are not carriers of cystic fibrosis mutations, abdominal US to assess for renal agenesis is indicated since these men have a higher chance of having absence of one of their kidneys'''
**** '''Estradiol'''
**** '''26% of males with unilateral congenital absence of the vas deferens and 11% of males with CBAVD had an absent ipsilateral kidney''';
***** '''Ratio of total T:E < 10:1 indicates reproductive dysfunction'''
***** Most of the bilateral CAVD patients with an absent ipsilateral kidney are in patients with no identifiable CF gene mutation.
**** '''Prolactin'''
** '''Varicoceles'''
***** '''Abolishes GnRH pulsatility, suppresses testosterone production'''
*** Large varicoceles are associated with greater preoperative impairment in semen quality than are small varicoceles
***** '''Pituitary disease (hyperplasia, adenoma, tumours), including prolactinoma, is associated with visual field changes, headache, and erectile dysfunction'''
*** Varicocele treatment may be more cost effective than assisted-reproductive therapy or can lower the intensity of treatment'''§'''
***** '''Obtain prolactin if clinically indicated. Consider MRI if very elevated.'''
*** '''See Varicocelectomy Chapter Notes'''
****** '''Prolactin is a labile assay. Before continuing with further diagnostic assessment or therapy, moderately elevated assay results should first be confirmed with a second test.'''
* '''Laboratory'''
** '''Semen analysis'''
** '''Serum'''
*** '''Results cannot precisely distinguish fertile from infertile men except in cases of azoospermia and some types of teratozoospermia (e.g., complete globozoospermia), necrozoospermia, or complete asthenozoospermia'''
*** '''Initial screen (6):'''
*** '''WHO semen parameter percentiles'''
***# '''Total testosterone'''
**** '''Derived from men whose partners became pregnant (fertile population) within 1 year of discontinuation of contraceptives.'''
***# '''SHBG'''
**** '''The 5th percentile is used to describe infertility cut-offs for 7 semen parameters'''
***# '''Albumin (to calculate bioavailable testosterone)'''
***** '''Values falling above or below the lower limit do not by themselves predict either fertility or infertility'''
***# '''LH'''
****** '''There are males who have abnormal semen parameters, yet they have contributed to a prior successful pregnancy through natural conception'''
***# '''FSH'''
****** '''Presence of abnormal semen parameters suggests the presence of a male factor in an infertile couple, encouraging physicians to consider further evaluation of the male and management to enhance male reproductive function'''
***# '''Estradiol'''
**# '''Volume <1.5mL'''
**** '''Prolactin, if clinically indicated.'''
**#* '''See 2015 CUA Azooospermia Guideline Notes'''
***** '''Total testosterone'''
**#* '''Causes:'''
****** '''≥300 ng/dL considered adequate (164 ng/dL bioavailable)'''
**#** '''Obstruction or hypoplasia (severe androgen deficiency, CBAVD) of the prostate and seminal vesicles'''
***** '''LH'''
**#** '''Retrograde ejaculation'''
****** '''Determine if hypoandrogenism testicular (primary) or pituitary (secondary) in nature'''
**#** '''Alpha blockers'''
***** '''FSH'''
**#** '''Spinal cord injury'''
****** '''Indirect assessment of germ cell mass'''
**#** '''Diabetes'''
******* '''If normal testicle size and FSH <7.6 IU/L --> consider obstructive azoospermia'''
**#** '''Multiple sclerosis'''
******* '''If reduced testicle size and FSH >7.6 IU/L --> consider spermatogenic dysfunction'''
**#* '''Hypervolemia (>5 mL), dilutes sperm therefore interferes with reproduction.'''
***** '''Estradiol'''
**#** '''IUI can be used to concentrate sperm'''
****** '''Ratio of total T:E < 10:1 indicates reproductive dysfunction'''
**# '''Concentration <15 million/mL'''
***** '''Prolactin'''
**#* '''Visual assessment under microscopy'''
****** '''Abolishes GnRH pulsatility, suppresses testosterone production'''
**# '''Total number <39 million/ejaculate'''
****** '''Pituitary disease (hyperplasia, adenoma, tumours), including prolactinoma, is associated with visual field changes, headache, and erectile dysfunction'''
**#* '''Most important semen analysis parameter'''
****** '''Obtain prolactin if clinically indicated. Consider MRI if very elevated.'''
**# '''Total motility <40%'''
******* '''Prolactin is a labile assay. Before continuing with further diagnostic assessment or therapy, moderately elevated assay results should first be confirmed with a second test.'''
**#* '''Visual assessment under microscopy'''
*** '''Semen analysis'''
**#* '''Asthenospermia is when total motility <40% or progressive motility <32%'''
**** '''Results cannot precisely distinguish fertile from infertile men except in cases of azoospermia and some types of teratozoospermia (e.g., complete globozoospermia), necrozoospermia, or complete asthenozoospermia'''
**#** '''Causes of asthenospermia§'''
**** '''WHO semen parameter percentiles'''
**#**# '''Sperm structural defects'''
***** '''Derived from men whose partners became pregnant (fertile population) within 1 year of discontinuation of contraceptives.'''
**#**# '''Prolonged abstinence periods'''
***** '''The 5th percentile is used to describe infertility cut-offs for 7 semen parameters'''
**#**# '''Genital tract infection'''
****** '''Values falling above or below the lower limit do not by themselves predict either fertility or infertility'''
**#**# '''Anti-sperm antibodies'''
******* '''There are males who have abnormal semen parameters, yet they have contributed to a prior successful pregnancy through natural conception'''
**#**# '''Partial ductal obstruction'''
******* '''Presence of abnormal semen parameters suggests the presence of a male factor in an infertile couple, encouraging physicians to consider further evaluation of the male and management to enhance male reproductive function'''
**#**# '''Varicocele'''
***# '''Volume <1.5mL'''
**# '''Progressive motility <32%'''
***#* '''See 2015 CUA Azooospermia Guideline Notes'''
**#* '''Progressive motility: moving actively, linearly or in large circle, regardless of speed'''
***#* '''Causes:'''
**#* '''Nonprogressive motility: all other patterns with absence of progressionNormal forms <4%Teratozoospermia: normal forms'''  
***#** '''Obstruction or hypoplasia (severe androgen deficiency, CBAVD) of the prostate and seminal vesicles'''
**# '''Normal forms <4%'''
***#** '''Retrograde ejaculation'''
**#* '''Teratozoospermia: normal forms <4%'''
***#** '''Alpha blockers'''
**#* '''Globospermia''': '''failure of acrosomal head to form small, round heads'''.
***#** '''Spinal cord injury'''
**#** Without the acrosome, fertilization with sperm in the natural setting or with incubational in vitro fertilization will not be successful. '''Intracytoplasmic sperm injection is required'''.
***#** '''Diabetes'''
**#*** Ejaculated sperm is available in this patient, and therefore surgical sperm extraction is unnecessary.
***#** '''Multiple sclerosis'''
**#* '''Higher rates of aneuploidy with many abnormal forms.'''
***#* '''Hypervolemia (>5 mL), dilutes sperm therefore interferes with reproduction.'''
**#** '''Conditions associated with aneuploidy:'''
***#** '''IUI can be used to concentrate sperm'''
**#*** Aging, cytotoxic agents, environemental exposures (smoking)
***# '''Concentration <15 million/mL'''
**#** '''Consider aneuploidy in patients with recurrent pregnancy losses'''
***#* '''Visual assessment under microscopy'''
**#** '''intracytoplasmic sperm injection with biological gametes is not recommended with sperm associated with macrocephaly and multiple tails due to the high rate of aneuploidy'''
***# '''Total number <39 million/ejaculate'''
**#* '''A variety of abnormal forms rules out excludes rare genetic conditions such as failure of formation of the acrosomal cap.'''
***#* '''Most important semen analysis parameter'''
**#* '''Strict morphology is not a consistent predictor of fertility, and for this reason, the AUA states that strict morphology “should not be used in isolation to make prognostic or therapeutic decisions'''
***# '''Total motility <40%'''
**# '''Vitality <58%'''
***#* '''Visual assessment under microscopy'''
Metabolically active living cells
***#* '''Asthenospermia is when total motility <40% or progressive motility <32%'''
***#** '''Causes of asthenospermia§'''
***#**# '''Sperm structural defects'''
***#**# '''Prolonged abstinence periods'''
***#**# '''Genital tract infection'''
***#**# '''Anti-sperm antibodies'''
***#**# '''Partial ductal obstruction'''
***#**# '''Varicocele'''
***# '''Progressive motility <32%'''
***#* '''Progressive motility: moving actively, linearly or in large circle, regardless of speed'''
***#* '''Nonprogressive motility: all other patterns with absence of progressionNormal forms <4%Teratozoospermia: normal forms'''
***# '''Normal forms <4%'''
***#* '''Teratozoospermia: normal forms <4%'''
***#* '''Globospermia''': '''failure of acrosomal head to form small, round heads'''.
***#** Without the acrosome, fertilization with sperm in the natural setting or with incubational in vitro fertilization will not be successful. '''Intracytoplasmic sperm injection is required'''.
***#*** Ejaculated sperm is available in this patient, and therefore surgical sperm extraction is unnecessary.
***#* '''Higher rates of aneuploidy with many abnormal forms.'''
***#** '''Conditions associated with aneuploidy:'''
***#*** Aging, cytotoxic agents, environemental exposures (smoking)
***#** '''Consider aneuploidy in patients with recurrent pregnancy losses'''
***#** '''intracytoplasmic sperm injection with biological gametes is not recommended with sperm associated with macrocephaly and multiple tails due to the high rate of aneuploidy'''
***#* '''A variety of abnormal forms rules out excludes rare genetic conditions such as failure of formation of the acrosomal cap.'''
***#* '''Strict morphology is not a consistent predictor of fertility, and for this reason, the AUA states that strict morphology “should not be used in isolation to make prognostic or therapeutic decisions'''
***# '''Vitality <58%'''


* Metabolically active living cells
'''Necrospermia: reduced vitality'''
* '''Necrospermia: reduced vitality'''
* '''Cannot evaluate in complete asthenospermia since assay relies on association of moving particles proximal to motile sperm'''
** '''Therefore, to rule out necrospermia when motility is 0%, consider vital stain'''
** '''In the complete absence of motility and necrospermia have been ruled out, electron microscopy can identify if ultrastructural tail defects are present in the immotile cilia syndrome'''
*** In immotile cilia syndrome is conrimed, patients can subsequently be counselled to undergo IVF


* '''Viscosity, coloration, pH'''
'''Cannot evaluate in complete asthenospermia since assay relies on association of moving particles proximal to motile sperm'''
** In spinal cord injury, a brown hue can be noted in the semen
* '''Therefore, to rule out necrospermia when motility is 0%, consider vital stain'''
** '''pH should be 7.2-7.8 (alkaline due to seminal vesicle contribution)'''
* '''In the complete absence of motility and necrospermia have been ruled out, electron microscopy can identify if ultrastructural tail defects are present in the immotile cilia syndrome'''
** In immotile cilia syndrome is conrimed, patients can subsequently be counselled to undergo IVF
'''Viscosity, coloration, pH'''
* In spinal cord injury, a brown hue can be noted in the semen
* '''pH should be 7.2-7.8 (alkaline due to seminal vesicle contribution)'''
'''Secondary semen analyses:'''
* '''Anti-sperm antibodies'''
** Varying clinical significance depending on degree of binding
** '''Associated with history of vasectomy, testis trauma, orchitis, cryptorchidism, testis cancer, varicocele'''
*** Vasectomy disrupts the blood-testis barrier, resulting in detectable levels of serum antisperm antibodies in 60% to 80% of men.
** '''Consider if semen analysis demonstrates sperm agglutination or reduced sperm motility'''
* '''Leukocytes'''
** '''Often present in the semen of infertile men. Should be < 1 million/mL'''
** '''Often indicate functional damage from DNA fragmentation''' to sperm membrane lipid peroxidation from reactive oxygen species released from the leukocytes; seldom due to antisperm antibodies or documentable infection.
** Leukocytes can occur with UTIs, but unless urine is in the semen, this is an unlikely source. '''Sexual transmitted infections can also lead to leukocytes in semen and this does need to be ruled-out,''' however, even PCR DNA testing for sexual transmitted pathogens are often negative verifying the '''situation is''' '''most commonly idiopathic'''
** '''Semen WBC staining is indicated only if increased numbers of round cells are noted in the semen'''
** '''Leukocytes and immature germ cells are not differentiable with light microscopy. A stain such as Papanicolaou allows them to be distinguished'''
* '''DNA fragmentation'''
** '''Direct measures of sperm DNA fragmentation include''' the terminal deoxynucleotidyl transferase dUTP nick end labeling '''(TUNEL) assay and the comet assay''' at neutral pH.
** '''AUA: Currently, the tests have inadequate sensitivity and specificity to be of value as screening tests for pregnancy by intercourse'''
*** '''The literature on outcomes associated with abnormally high sperm DNA fragmentation levels is inconsistent'''
**** Some investigators hypothesize that abnormally high levels of sperm DNA fragmentation are associated with abnormal reproductive outcomes, including lower fertilization, pregnancy, live birth rates, and higher rates of miscarriage.
*** At this time, the WHO categorizes sperm DNA integrity tests as "research procedures"'''.'''
** '''Currently no effective therapy to correct an abnormal DNA fragmentation result'''
* '''Sperm penetration assay''' most closely models incubational in vitro fertilization
* '''Sperm culture: limited seminal concentrations of the majority of bacteria including E. Coli have minimal or no effects on sperm motility in vivo'''


* '''Secondary semen analyses:'''
== Genetic testing ==
** '''Anti-sperm antibodies'''
* '''Karyotype'''
*** Varying clinical significance depending on degree of binding
** '''Indicated in all men with azoospermia and severe oligospermia (<5 million sperm/mL)'''
*** '''Associated with history of vasectomy, testis trauma, orchitis, cryptorchidism, testis cancer, varicocele'''
* '''Y Chromosome Microdeletion'''
**** Vasectomy disrupts the blood-testis barrier, resulting in detectable levels of serum antisperm antibodies in 60% to 80% of men.
** '''A region in the long arm of the Y chromosome critical to formation of sperm is known as AZF – azoospermia factor'''
*** '''Consider if semen analysis demonstrates sperm agglutination or reduced sperm motility'''
** '''AZFa (also known as AZF1) or AZFb microdeletion: generally result in absence of spermatogenesis.'''
** '''Leukocytes'''
*** Common phenotypic manifestations of deletions in AZFa region are azoospermia and Sertoli cell-only syndrome
*** '''Often present in the semen of infertile men. Should be < 1 million/mL'''
*** Genes in the AZFb region have been found to support the growth and maturity of sperm and are critical for efficient progression of spermatogenesis. Common phenotypic manifestations of deletions in this region are spermatogenic arrest and azoospermia
*** '''Often indicate functional damage from DNA fragmentation''' to sperm membrane lipid peroxidation from reactive oxygen species released from the leukocytes; seldom due to antisperm antibodies or documentable infection.
** '''AZFc microdeletion: may result in spermatogenic impairment but not necessarily absence of spermatogenesis'''
*** Leukocytes can occur with UTIs, but unless urine is in the semen, this is an unlikely source. '''Sexual transmitted infections can also lead to leukocytes in semen and this does need to be ruled-out,''' however, even PCR DNA testing for sexual transmitted pathogens are often negative verifying the '''situation is''' '''most commonly idiopathic'''
*** Genes in the AZFc region have a diverse role, but overall, they are essential to complete spermatogenesis. AZFc deletions have been associated with drastic reduction in sperm count, and there are subsets of men with AZFc microdeletions that experience progressive declines in their sperm count.
*** '''Semen WBC staining is indicated only if increased numbers of round cells are noted in the semen'''
** '''Originally, the AZFb and AZFc genes were identified and thought to be separate regions. They were later found to be overlapping and are now referred to as AZF2.'''
*** '''Leukocytes and immature germ cells are not differentiable with light microscopy. A stain such as Papanicolaou allows them to be distinguished'''
** '''Should be done in azoospermia before surgical sperm extraction to counsel likelihood of retrieval'''
** '''DNA fragmentation'''
*** '''Direct measures of sperm DNA fragmentation include''' the terminal deoxynucleotidyl transferase dUTP nick end labeling '''(TUNEL) assay and the comet assay''' at neutral pH.
*** '''AUA: Currently, the tests have inadequate sensitivity and specificity to be of value as screening tests for pregnancy by intercourse'''
**** '''The literature on outcomes associated with abnormally high sperm DNA fragmentation levels is inconsistent'''
***** Some investigators hypothesize that abnormally high levels of sperm DNA fragmentation are associated with abnormal reproductive outcomes, including lower fertilization, pregnancy, live birth rates, and higher rates of miscarriage.
**** At this time, the WHO categorizes sperm DNA integrity tests as "research procedures"'''.'''
*** '''Currently no effective therapy to correct an abnormal DNA fragmentation result'''
** '''Sperm penetration assay''' most closely models incubational in vitro fertilization
** '''Sperm culture: limited seminal concentrations of the majority of bacteria including E. Coli have minimal or no effects on sperm motility in vivo'''


* '''Genetic testing'''
== Imaging ==
** '''Karyotype'''
* '''Scrotal Ultrasound: testicular size, varicoceles'''
*** '''Indicated in all men with azoospermia and severe oligospermia (<5 million sperm/mL)'''
* '''TRUS: suggestive of ejaculatory duct obstruction if AP diameter of seminal vesicle >1.5cm'''
** '''Y Chromosome Microdeletion'''
* '''Vasography: patency of vas'''.
*** '''A region in the long arm of the Y chromosome critical to formation of sperm is known as AZF – azoospermia factor'''
* '''MRI brain: evaluate for functioning and non-functioning pituitary tumors in secondary hypogonadotropic hypogonadism with a elevated or normal serum prolactin level'''
*** '''AZFa (also known as AZF1) or AZFb microdeletion: generally result in absence of spermatogenesis.'''
** '''2018 AUA Testosterone Deficiency Guidelines: total testosterone <150 ng/dL in combination with a low or low/normal LH should undergo a pituitary MRI regardless of prolactin levels, as non-secreting adenomas may be identified.'''
**** Common phenotypic manifestations of deletions in AZFa region are azoospermia and Sertoli cell-only syndrome
**** Genes in the AZFb region have been found to support the growth and maturity of sperm and are critical for efficient progression of spermatogenesis. Common phenotypic manifestations of deletions in this region are spermatogenic arrest and azoospermia
*** '''AZFc microdeletion: may result in spermatogenic impairment but not necessarily absence of spermatogenesis'''
**** Genes in the AZFc region have a diverse role, but overall, they are essential to complete spermatogenesis. AZFc deletions have been associated with drastic reduction in sperm count, and there are subsets of men with AZFc microdeletions that experience progressive declines in their sperm count.
*** '''Originally, the AZFb and AZFc genes were identified and thought to be separate regions. They were later found to be overlapping and are now referred to as AZF2.'''
*** '''Should be done in azoospermia before surgical sperm extraction to counsel likelihood of retrieval'''
* '''Imaging'''
** '''Scrotal Ultrasound: testicular size, varicoceles'''
** '''TRUS: suggestive of ejaculatory duct obstruction if AP diameter of seminal vesicle >1.5cm'''
** '''Vasography: patency of vas'''.
** '''MRI brain: evaluate for functioning and non-functioning pituitary tumors in secondary hypogonadotropic hypogonadism with a elevated or normal serum prolactin level'''
*** '''2018 AUA Testosterone Deficiency Guidelines: total testosterone <150 ng/dL in combination with a low or low/normal LH should undergo a pituitary MRI regardless of prolactin levels, as non-secreting adenomas may be identified.'''
* '''Testicular biopsy'''
** '''Indications (must have all):'''
**# '''Azoospermic'''
**# '''Testis of normal size and consistency'''
**# '''Palpable vasa deferentia'''
**# '''Normal serum follicle-stimulating hormone (FSH) levels'''
**# '''Negative serum anti-sperm antibody assay'''
**# '''Biopsy will distinguish obstructive from nonobstructive azoospermia'''
** '''In men with congenital absence of vasa and normal serum FSH levels, biopsy is not needed since these patient’s azoospermia is likely obstructive rather than testicular in cause'''
** Spermatogenesis may be highly focal in men with azoospermia so a random biopsy may miss areas of sperm production


===== References =====
== Testicular biopsy ==
* '''Indications (must have all):'''
*# '''Azoospermic'''
*# '''Testis of normal size and consistency'''
*# '''Palpable vasa deferentia'''
*# '''Normal serum follicle-stimulating hormone (FSH) levels'''
*# '''Negative serum anti-sperm antibody assay'''
*# '''Biopsy will distinguish obstructive from nonobstructive azoospermia'''
* '''In men with congenital absence of vasa and normal serum FSH levels, biopsy is not needed since these patient’s azoospermia is likely obstructive rather than testicular in cause'''
* Spermatogenesis may be highly focal in men with azoospermia so a random biopsy may miss areas of sperm production
== References ==


* Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 24
* Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 24
*[https://pubmed.ncbi.nlm.nih.gov/33295257/ Schlegel, Peter N., et al. "Diagnosis and treatment of infertility in men: AUA/ASRM guideline part I." ''The Journal of urology'' 205.1 (2021): 36-43.]

Revision as of 16:27, 19 January 2024

See 2020 AUA/ASRM Guidelines on Infertility

See 2015 CUA Azoospermia Guideline Notes

General principles

  • Goals of evaluation are to identify (5):§
    1. Potentially correctable conditions for treatment to allow for conception through intercourse or through techniques, such as IUI or IVF, when those approaches would otherwise not be possible
    2. Irreversible conditions that are amenable to ART using the sperm of the male partner
    3. irreversible conditions that are not amenable to the above, and for which donor insemination or adoption are possible options
    4. Life- or health-threatening conditions that may underlie the infertility or associated medical comorbidities that require medical attention
      • Male infertility may occasionally be the presenting manifestation of an underlying life-threatening condition such as testicular cancer or pituitary tumours
    5. Genetic abnormalities or lifestyle and age factors that may affect the health of the male patient or of offspring particularly if ART are to be employed
  • For initial infertility evaluation, both male and female partners should undergo concurrent assessment.
    • Many couples have more than one fertility issue present.
      • For the female partner, tests are indicated to evaluate ovarian reserve, ovulatory function, tubal structures as well as assessment of the uterine cavity.
      • For the male partner, good clinical practice to obtain a reproductive history, perform a physical examination and basic diagnostic tests of reproductive function (Appendix I).
  • In couples with failed assisted reproductive technology cycles or recurrent pregnancy losses (RPL) (two or more losses), evaluation of the male should be considered.
  • Timing
    • Infertility should be evaluated after 6 months of attempted conception when the female partner is over 35 years of age

UrologySchool.com Summary

  • History and physical exam
  • Labs
    • Semen analysis
      • At least two SAs obtained a month apart are important to consider, especially if the first SA has abnormalparameters.§

History and physical exam

History

  • Evaluation of men with secondary infertility should include a focus on conditions or exposures that have developed or occurred after initiation of the earlier pregnancy(ies).§
  • Risk factors
    • Can be categorized into (TICS - see Infertility: Epidemiology and Etiology Chapter Notes):
      1. Toxins (medications, chemotherapy, radiation, social habits)
      2. Infections of the GU tract
      3. Childhood (congenital causes (recall DUNKY-XX), hydrocele or hernia surgery, trosion, cryptorchidism)
      4. Sexual history (lubricants)
  • Infertility history
    • Duration of infertility
    • Whether the infertility is primary or secondary
    • Any treatments to date
    • Libido, sexual function, sexual activity
  • General health of the male (diabetes, respiratory issues, recent illnesses)
    • Medical comorbidities (e.g., hypertension, hyperlipidemia, obesity, diabetes) that can contribute to infertility.
    • If there has been a recent serious medical illness or injury or evidence of a recent reproductive tract infection, semen testing should be repeated at least 3 months following recovery from the illness
  • Surgery of the reproductive tract: testis cancer, undescended testis, hydrocelectomies, spermatocelectomies, varicocelectomies, vasectomies
    • Vasectomy reversal may represent a more cost-effective option compared to IVF in couples with adequate ovarian function§
  • Proven or suspected GU infections/inflammation: sexually transmitted infections, epididymo-orchitis, mumps orchitis
  • Medications and therapies which might have an adverse impact on spermatogenesis
    • See Infertility: Epidemiology and Etiology Chapter Notes
    • If there has been exposure to any gonadotoxic agents, these medications should be stopped and semen should be retested in 3-6 months
  • Environmental exposures (pesticides, excessive heat on the testicles)
  • Lifestyle (cigarette smoking, recreational drugs, alcohol use, stress, anabolic steroid usel)
  • History of any genetic abnormalities in the patient or the family

Physical exam

  • Body habitus
    • Obese men have
      • Elevated estradiol
        • Mechanism: adipose cells have aromatase which metabolizes testosterone to estradiol
      • Reduced serum testosterone and reduced SHBG (therefore, more bioavailable testosterone component of total testosterone)
  • State of virilisation
  • Abdominal examination
    • Scars indicative of previous inguinal surgery or treatment of undescended testis
  • Scrotal examination
    • Size and consistency of the testis; size correlates well with sperm production
      • Long axis length <4.6cm associated with impaired spermatogenesis
      • Volume <20mL considered low
    • Epididymis (engorgement may suggest obstruction)
  • Phallus (meatal displacement)
  • Prostate and seminal vesicles
  • Vas deferens
    • Unilateral absence
      • Suggests complete lack of Wolffian (duct development on that side, including renal agenesis.
        • The absent vas should raise a red flag for possible ipsilateral renal agenesis because the ureteral bud and vas are both derived from the wolffian duct
        • Recall, male structures derived from Wolffian ducts:
          • Body and tail of epididymis (note efferent ductules and head of epididymis from mesonephric tubules)
          • Vas deferens
          • Seminal vesicles
            • Distally, the wolffian ducts join the urogenital sinus by about 30 days gestation, where they develop into the seminal vesicles
          • Ejaculatory duct
          • Appendix epididymis
        • Male structures derived from Müllerian duct (2):
          1. Appendix testis
          2. Prostatic utricle
        • Male structures derived from urogenital sinus:
          1. Prostate
          2. Bulbourethral glands
    • Bilateral absence
      • Consider investigation for CF gene mutation
        • Congenital bilateral absence of the vas deferens (CBAVD) is associated with CF gene mutations in 85% of patients.
          • The most common CFTR mutation is ΔF508, which is severe
          • ≈7% of brothers of patients with CBAVD will have also vasal agenesis
          • No association between CBAVD and Y microdeletions.
        • If the male partner is being tested for CFTR, such is in CBAVD, both patient and female partner should be tested for CFTR to determine risk of cystic fibrosis in offspring (CUA Azoospermia Guidelines).
          • Only a portion of CFTR mutations are detected by routine testing.
            • A male with CBAVD should be assumted to be a CFTR carrier despite a negative CFTR gene test and the female partner still needs to be tested prior to any assisted reproductive techniques.
      • Semen is almost always of low volume and acidic in patients with CBAVD due to hypoplasia or absence of the seminal vesicles, which provide alkalinity
    • In men with congenital bilateral or unilateral absence of the vas deferens who are not carriers of cystic fibrosis mutations, abdominal US to assess for renal agenesis is indicated since these men have a higher chance of having absence of one of their kidneys
      • 26% of males with unilateral congenital absence of the vas deferens and 11% of males with CBAVD had an absent ipsilateral kidney;
        • Most of the bilateral CAVD patients with an absent ipsilateral kidney are in patients with no identifiable CF gene mutation.
  • Varicoceles
    • Large varicoceles are associated with greater preoperative impairment in semen quality than are small varicoceles
    • Varicocele treatment may be more cost effective than assisted-reproductive therapy or can lower the intensity of treatment§
    • See Varicocelectomy Chapter Notes

Laboratory

  • Serum
    • Initial screen (6):
      1. Total testosterone
      2. SHBG
      3. Albumin (to calculate bioavailable testosterone)
      4. LH
      5. FSH
      6. Estradiol
      • Prolactin, if clinically indicated.
        • Total testosterone
          • ≥300 ng/dL considered adequate (164 ng/dL bioavailable)
        • LH
          • Determine if hypoandrogenism testicular (primary) or pituitary (secondary) in nature
        • FSH
          • Indirect assessment of germ cell mass
            • If normal testicle size and FSH <7.6 IU/L --> consider obstructive azoospermia
            • If reduced testicle size and FSH >7.6 IU/L --> consider spermatogenic dysfunction
        • Estradiol
          • Ratio of total T:E < 10:1 indicates reproductive dysfunction
        • Prolactin
          • Abolishes GnRH pulsatility, suppresses testosterone production
          • Pituitary disease (hyperplasia, adenoma, tumours), including prolactinoma, is associated with visual field changes, headache, and erectile dysfunction
          • Obtain prolactin if clinically indicated. Consider MRI if very elevated.
            • Prolactin is a labile assay. Before continuing with further diagnostic assessment or therapy, moderately elevated assay results should first be confirmed with a second test.
    • Semen analysis
      • Results cannot precisely distinguish fertile from infertile men except in cases of azoospermia and some types of teratozoospermia (e.g., complete globozoospermia), necrozoospermia, or complete asthenozoospermia
      • WHO semen parameter percentiles
        • Derived from men whose partners became pregnant (fertile population) within 1 year of discontinuation of contraceptives.
        • The 5th percentile is used to describe infertility cut-offs for 7 semen parameters
          • Values falling above or below the lower limit do not by themselves predict either fertility or infertility
            • There are males who have abnormal semen parameters, yet they have contributed to a prior successful pregnancy through natural conception
            • Presence of abnormal semen parameters suggests the presence of a male factor in an infertile couple, encouraging physicians to consider further evaluation of the male and management to enhance male reproductive function
      1. Volume <1.5mL
        • See 2015 CUA Azooospermia Guideline Notes
        • Causes:
          • Obstruction or hypoplasia (severe androgen deficiency, CBAVD) of the prostate and seminal vesicles
          • Retrograde ejaculation
          • Alpha blockers
          • Spinal cord injury
          • Diabetes
          • Multiple sclerosis
        • Hypervolemia (>5 mL), dilutes sperm therefore interferes with reproduction.
          • IUI can be used to concentrate sperm
      2. Concentration <15 million/mL
        • Visual assessment under microscopy
      3. Total number <39 million/ejaculate
        • Most important semen analysis parameter
      4. Total motility <40%
        • Visual assessment under microscopy
        • Asthenospermia is when total motility <40% or progressive motility <32%
          • Causes of asthenospermia§
            1. Sperm structural defects
            2. Prolonged abstinence periods
            3. Genital tract infection
            4. Anti-sperm antibodies
            5. Partial ductal obstruction
            6. Varicocele
      5. Progressive motility <32%
        • Progressive motility: moving actively, linearly or in large circle, regardless of speed
        • Nonprogressive motility: all other patterns with absence of progressionNormal forms <4%Teratozoospermia: normal forms
      6. Normal forms <4%
        • Teratozoospermia: normal forms <4%
        • Globospermia: failure of acrosomal head to form small, round heads.
          • Without the acrosome, fertilization with sperm in the natural setting or with incubational in vitro fertilization will not be successful. Intracytoplasmic sperm injection is required.
            • Ejaculated sperm is available in this patient, and therefore surgical sperm extraction is unnecessary.
        • Higher rates of aneuploidy with many abnormal forms.
          • Conditions associated with aneuploidy:
            • Aging, cytotoxic agents, environemental exposures (smoking)
          • Consider aneuploidy in patients with recurrent pregnancy losses
          • intracytoplasmic sperm injection with biological gametes is not recommended with sperm associated with macrocephaly and multiple tails due to the high rate of aneuploidy
        • A variety of abnormal forms rules out excludes rare genetic conditions such as failure of formation of the acrosomal cap.
        • Strict morphology is not a consistent predictor of fertility, and for this reason, the AUA states that strict morphology “should not be used in isolation to make prognostic or therapeutic decisions
      7. Vitality <58%

Metabolically active living cells

Necrospermia: reduced vitality

Cannot evaluate in complete asthenospermia since assay relies on association of moving particles proximal to motile sperm

  • Therefore, to rule out necrospermia when motility is 0%, consider vital stain
  • In the complete absence of motility and necrospermia have been ruled out, electron microscopy can identify if ultrastructural tail defects are present in the immotile cilia syndrome
    • In immotile cilia syndrome is conrimed, patients can subsequently be counselled to undergo IVF

Viscosity, coloration, pH

  • In spinal cord injury, a brown hue can be noted in the semen
  • pH should be 7.2-7.8 (alkaline due to seminal vesicle contribution)

Secondary semen analyses:

  • Anti-sperm antibodies
    • Varying clinical significance depending on degree of binding
    • Associated with history of vasectomy, testis trauma, orchitis, cryptorchidism, testis cancer, varicocele
      • Vasectomy disrupts the blood-testis barrier, resulting in detectable levels of serum antisperm antibodies in 60% to 80% of men.
    • Consider if semen analysis demonstrates sperm agglutination or reduced sperm motility
  • Leukocytes
    • Often present in the semen of infertile men. Should be < 1 million/mL
    • Often indicate functional damage from DNA fragmentation to sperm membrane lipid peroxidation from reactive oxygen species released from the leukocytes; seldom due to antisperm antibodies or documentable infection.
    • Leukocytes can occur with UTIs, but unless urine is in the semen, this is an unlikely source. Sexual transmitted infections can also lead to leukocytes in semen and this does need to be ruled-out, however, even PCR DNA testing for sexual transmitted pathogens are often negative verifying the situation is most commonly idiopathic
    • Semen WBC staining is indicated only if increased numbers of round cells are noted in the semen
    • Leukocytes and immature germ cells are not differentiable with light microscopy. A stain such as Papanicolaou allows them to be distinguished
  • DNA fragmentation
    • Direct measures of sperm DNA fragmentation include the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and the comet assay at neutral pH.
    • AUA: Currently, the tests have inadequate sensitivity and specificity to be of value as screening tests for pregnancy by intercourse
      • The literature on outcomes associated with abnormally high sperm DNA fragmentation levels is inconsistent
        • Some investigators hypothesize that abnormally high levels of sperm DNA fragmentation are associated with abnormal reproductive outcomes, including lower fertilization, pregnancy, live birth rates, and higher rates of miscarriage.
      • At this time, the WHO categorizes sperm DNA integrity tests as "research procedures".
    • Currently no effective therapy to correct an abnormal DNA fragmentation result
  • Sperm penetration assay most closely models incubational in vitro fertilization
  • Sperm culture: limited seminal concentrations of the majority of bacteria including E. Coli have minimal or no effects on sperm motility in vivo

Genetic testing

  • Karyotype
    • Indicated in all men with azoospermia and severe oligospermia (<5 million sperm/mL)
  • Y Chromosome Microdeletion
    • A region in the long arm of the Y chromosome critical to formation of sperm is known as AZF – azoospermia factor
    • AZFa (also known as AZF1) or AZFb microdeletion: generally result in absence of spermatogenesis.
      • Common phenotypic manifestations of deletions in AZFa region are azoospermia and Sertoli cell-only syndrome
      • Genes in the AZFb region have been found to support the growth and maturity of sperm and are critical for efficient progression of spermatogenesis. Common phenotypic manifestations of deletions in this region are spermatogenic arrest and azoospermia
    • AZFc microdeletion: may result in spermatogenic impairment but not necessarily absence of spermatogenesis
      • Genes in the AZFc region have a diverse role, but overall, they are essential to complete spermatogenesis. AZFc deletions have been associated with drastic reduction in sperm count, and there are subsets of men with AZFc microdeletions that experience progressive declines in their sperm count.
    • Originally, the AZFb and AZFc genes were identified and thought to be separate regions. They were later found to be overlapping and are now referred to as AZF2.
    • Should be done in azoospermia before surgical sperm extraction to counsel likelihood of retrieval

Imaging

  • Scrotal Ultrasound: testicular size, varicoceles
  • TRUS: suggestive of ejaculatory duct obstruction if AP diameter of seminal vesicle >1.5cm
  • Vasography: patency of vas.
  • MRI brain: evaluate for functioning and non-functioning pituitary tumors in secondary hypogonadotropic hypogonadism with a elevated or normal serum prolactin level
    • 2018 AUA Testosterone Deficiency Guidelines: total testosterone <150 ng/dL in combination with a low or low/normal LH should undergo a pituitary MRI regardless of prolactin levels, as non-secreting adenomas may be identified.

Testicular biopsy

  • Indications (must have all):
    1. Azoospermic
    2. Testis of normal size and consistency
    3. Palpable vasa deferentia
    4. Normal serum follicle-stimulating hormone (FSH) levels
    5. Negative serum anti-sperm antibody assay
    6. Biopsy will distinguish obstructive from nonobstructive azoospermia
  • In men with congenital absence of vasa and normal serum FSH levels, biopsy is not needed since these patient’s azoospermia is likely obstructive rather than testicular in cause
  • Spermatogenesis may be highly focal in men with azoospermia so a random biopsy may miss areas of sperm production

References

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