Infertility: Diagnosis and Evaluation: Difference between revisions

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* '''See [https://www.auanet.org/documents/Guidelines/PDF/Male-Infertility-Algorithm.pdf Algorithm from Original Guidelines]'''

*See [https://www.youtube.com/watch?v=6d0TZRTQLJ8 Video Reviewing Guidelines] (Dr. Joshua Helpern)

'''See 2015 CUA Azoospermia Guideline Notes'''

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* '''Labs'''

** '''Semen analysis'''

*** '''At least two SAs obtained a month apart are important to consider, especially if the first SA has abnormal parameters'''

*** '''At least two SAs obtained a month apart are important to consider, especially if the first SA has abnormal parameters[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

****'''Semen parameters are highly variable biological measures and may vary substantially from test to test'''

****'''Up to 35% of men with non-obstructive azoospermia will have sperm detected on subsequent SA without medical intervention[https://pubmed.ncbi.nlm.nih.gov/9222005/]'''

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***#'''Atrophic testes'''

***#'''Evidence of hormonal abnormality on physical evaluation'''

****'''If testosterone low (<300ng/mL), get (3)'''

****'''If testosterone low (<300ng/mL), get (5)'''

****#'''Repeat measurement of total testosterone (or bioavailable testosterone)'''

****#'''Free (or bioavailable) testosterone'''

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****#'''Prolactin levels'''

**'''Genetic testing, if indicated (see below)'''

***'''Karyotype and Y-microsome deletion, if (3):'''

***'''Karyotype and Y-microsome deletion, if'''

***#'''Azoospermia or severe oligozoospermia (<5 million sperm/mL) with elevated FSH'''

****'''Primary infertility and (3):'''

***#'''Testicular atrophy'''

****#'''Azoospermia or severe oligozoospermia (<5 million sperm/mL) with elevated FSH OR'''

***#'''Presumed diagnosis of impaired sperm production as the cause of azoospermia'''

****#'''Testicular atrophy OR'''

***'''Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation carrier testing (including assessment of the 5T allele), if (2):'''

****#'''Presumed diagnosis of impaired sperm production as the cause of azoospermia'''

***'''Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation carrier testing (including assessment of the 5T allele), if (3):'''

***#'''Vasal agenesis (unilateral or bilateral)'''

***#'''Idiopathic obstructive azoospermia'''

***#'''If the female partner is a carrier (to consider for preimplantation diagnosis)'''

*'''Imaging'''

**'''Renal ultrasound, if ~~vasal~~ agenesis'''

**'''Renal ultrasound, if (1):'''

**'''Trans-rectal ultrasound, if'''

**#'''Vasal agenesis'''

**#'''Low volume azoospermia or significant asthenospermia'''

**'''Trans-rectal ultrasound, if (3):'''

**#'''Low semen volume with azoospermia and palpable vasa OR'''

**#'''Low semen volume and significant asthenospermia (total motility <40% or progressive motility <32%) OR'''

**#'''Symptoms (e.g. painful ejaculation)'''

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*** '''Penile plaque''' as in Peyronie’s disease may make it difficult for vaginal intercourse

*** '''Penile lesions/ulcers/discharge''' may be a sign of sexually transmitted infection

**'''Scrotum'''

**'''Scrotum (5)'''

*** '''Scars''' suggest previous scrotal surgery/trauma

**# '''Scars''' suggest previous scrotal surgery/trauma

***'''Testis'''

**#'''Testis'''

****'''Size and consistency of the testis; size correlates well with sperm production'''

**#*'''Size and consistency of the testis; size correlates well with sperm production'''

***** '''Long axis length <4.6cm associated with impaired spermatogenesis'''

**#** '''Long axis length <4.6cm associated with impaired spermatogenesis'''

***** '''Volume <20mL considered low'''

**#** '''Volume <20mL considered low'''

*****Obstructive azoospermia is suspected if the physical examination reveals testes of normal size, fully descended into the scrotum and bilaterally indurated epididymides with or without absence of the vas deferens

**#**Obstructive azoospermia is suspected if the physical examination reveals testes of normal size, fully descended into the scrotum and bilaterally indurated epididymides with or without absence of the vas deferens

*****'''When the testes are atrophied and soft, especially in the presence of FSH greater than 7.6 IU/L, the results are suggestive of spermatogenic failure rather than obstructive azoospermia.'''

**#**'''When the testes are atrophied and soft, especially in the presence of FSH greater than 7.6 IU/L, the results are suggestive of spermatogenic failure rather than obstructive azoospermia.'''

**** Location as scrotal position of the testes is important for normal function

**#* Location as scrotal position of the testes is important for normal function

**** Exam may also reveal masses consistent with a testicular cancer

**#* Exam may also reveal masses consistent with a testicular cancer

*** '''Epididymides'''

**# '''Vas deferens'''

**** Shape/consistency as normal development should be identified to determine atresia that could be identified by the presence of a ''CFTR'' mutation.

**#* Shape/consistency as normal development and contour should be confirmed to rule out agenesis as may be seen in the presence of a ''CFTR'' mutation or aberrant Wolffian duct embryogenesis

**** Induration/dilation could suggest obstruction.

**#**'''Unilateral absence'''

**** Epididymal cysts or spermatoceles may also lead to obstruction.

**#*** '''Suggests complete lack of Wolffian duct development on that side, including renal agenesis'''

~~***~~ '''Vas deferens'''

**#**** '''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'''

**** Shape/consistency as normal development and contour should be confirmed to rule out agenesis as may be seen in the presence of a ''CFTR'' mutation or aberrant Wolffian duct embryogenesis

**#**** '''Recall, male structures derived from Wolffian ducts:'''

*****'''Unilateral absence'''

**#****# '''Body and tail of epididymis (note efferent ductules and head of epididymis from mesonephric tubules)'''

****** '''Suggests complete lack of Wolffian duct development on that side, including renal agenesis'''

**#****# '''Vas deferens'''

******* '''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'''

**#****# '''Seminal vesicles'''

******* '''Recall, male structures derived from Wolffian ducts:'''

**#****#* Distally, the wolffian ducts join the urogenital sinus by about 30 days gestation, where they develop into the seminal vesicles

*******# '''Body and tail of epididymis (note efferent ductules and head of epididymis from mesonephric tubules)'''

**#****# '''Ejaculatory duct'''

*******# '''Vas deferens'''

**#****# '''Appendix epididymis'''

*******# '''Seminal vesicles'''

**#**** '''Male structures derived from Müllerian duct (2):'''

*******#* Distally, the wolffian ducts join the urogenital sinus by about 30 days gestation, where they develop into the seminal vesicles

**#****#'''Appendix testis'''

*******# '''Ejaculatory duct'''

**#****#'''Prostatic utricle'''

*******# '''Appendix epididymis'''

**#**** '''Male structures derived from urogenital sinus:'''

******* '''Male structures derived from Müllerian duct (2):'''

**#****# '''Prostate'''

*******#'''Appendix testis'''

**#****# '''Bulbourethral glands'''

*******#'''Prostatic utricle'''

**#** '''Bilateral absence'''

******* '''Male structures derived from urogenital sinus:'''

**#*** '''Consider investigation for CF gene mutation'''

*******# '''Prostate'''

**#**** '''Mutations in the ''CFTR'' gene are present in up to 80% of men with congenital bilateral absence of the vas deferens (CBAVD), 20% of men with''' '''congenital''' '''unilateral absence of the vas deferens''' and 21% of men with idiopathic epididymal obstruction[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]

*******# '''Bulbourethral glands'''

**#***** Most common CFTR mutation is ΔF508, which is severe

***** '''Bilateral absence'''

**#***** ≈7% of brothers of patients with CBAVD will have also vasal agenesis

****** '''Consider investigation for CF gene mutation'''

**#***** No association between CBAVD and Y microdeletions.

******* '''Mutations in the ''CFTR'' gene are present in up to 80% of men with congenital bilateral absence of the vas deferens (CBAVD), 20% of men with''' '''congenital''' '''unilateral absence of the vas deferens''' and 21% of men with idiopathic epididymal obstruction[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]

**#**** '''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).'''

******** Most common CFTR mutation is ΔF508, which is severe

**#***** '''Only a portion of CFTR mutations are detected by routine testing.'''

******** ≈7% of brothers of patients with CBAVD will have also vasal agenesis

**#****** '''A male with CBAVD should be assumed 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.'''

******** No association between CBAVD and Y microdeletions.

**#*** '''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 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).'''

**#** '''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'''

******** '''Only a portion of CFTR mutations are detected by routine testing.'''

**#*** '''26% of males with unilateral congenital absence of the vas deferens and 11% of males with CBAVD had an absent ipsilateral kidney''';

********* '''A male with CBAVD should be assumed 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.'''

**#**** Most of the bilateral CAVD patients with an absent ipsilateral kidney are in patients with no identifiable CF gene mutation.

****** '''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'''

**#* Presence/location of any vasectomy defect or granuloma should also be assessed

***** '''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'''

**#'''Epididymides'''

****** '''26% of males with unilateral congenital absence of the vas deferens and 11% of males with CBAVD had an absent ipsilateral kidney''';

**#* Shape/consistency as normal development should be identified to determine atresia that could be identified by the presence of a ''CFTR'' mutation.

******* Most of the bilateral CAVD patients with an absent ipsilateral kidney are in patients with no identifiable CF gene mutation.

**#* Induration/dilation could suggest obstruction.

**** Presence/location of any vasectomy defect or granuloma should also be assessed

**#* Epididymal cysts or spermatoceles may also lead to obstruction.

***'''Varicoceles'''

**#'''Varicoceles'''

**** Large varicoceles are associated with greater preoperative impairment in semen quality than small varicoceles

**#* Potential mechanisms of varicocele contributing to infertility

**** Varicocele treatment may be more cost effective than assisted-reproductive therapy or can lower the intensity of treatment'''§'''

**#**Hyperthermia

**** '''See [[Varicocele]] Chapter Notes'''

**#**Testicular hormonal imbalance

**#**Increased reactive oxygen species

**#**Hypoperfusion leading to hypoxia

**#*

**#*Large varicoceles are associated with greater preoperative impairment in semen quality than small varicoceles

**#* Varicocele treatment may be more cost effective than assisted-reproductive therapy or can lower the intensity of treatment'''§'''

**#* '''See [[Varicocele]] Chapter Notes'''

** '''Digital rectal exam'''

*** '''Midline prostatic cysts or dilated seminal vesicles''' may assist in the diagnosis of ejaculatory duct obstruction

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**#'''Complete asthenozoospermia'''

**#'''Some types of teratozoospermia (e.g., complete globozoospermia)'''

*'''Should be examined under the microscope within one hour of collection'''

*'''Should be given after 2-3 days of abstinence'''

*'''Number of samples'''

**'''At least two semen analyses obtained a month apart are important to consider, especially if the first SA has abnormal parameters[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

***'''If azoospermia, a second SA should be performed at least one to two weeks later.'''

==== WHO semen parameter percentiles ====

* '''Derived from men whose partners became pregnant (fertile population) within 1 year of discontinuation of contraceptives.'''

* '''except in cases of azoospermia and some types of teratozoospermia (e.g., complete globozoospermia), necrozoospermia, or complete asthenozoospermia'''

* '''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;''' '''males with''' '''abnormal semen parameters have contributed to a prior successful pregnancy through natural conception'''

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#*'''If semen analysis shows azoospermia, laboratory should then centrifuge the ejaculate and re-suspend the pellet in a small volume of seminal plasma and examine under wet mount microscopy for the presence of rare sperm.'''

#**'''If no sperm are present, a second semen analysis should be performed at least one to two weeks later. If the sample is azoospermic, then another pellet analysis should be performed.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

#**'''Further investigations for azoospermia depend on if it is associated with low-volume (obstructive) azoospermia or normal-volume azoospermia'''

#*'''Azoospermic patients with[https://pubmed.ncbi.nlm.nih.gov/15363709/ §]'''

#**'''Normal ejaculate volume may have either obstruction of the reproductive system or abnormalities of spermatogenesis'''

#**'''Low semen volume and normal sized testes may have ejaculatory dysfunction or ejaculatory duct obstruction'''

#'''Concentration <15 million/mL'''

#* Visual assessment under microscopy

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#'''Total motility <40%'''

#* '''Visual assessment under microscopy'''

#* '''Asthenospermia is when total motility <40% or progressive motility <32%'''

#* '''Asthenospermia is when total motility <40% or progressive motility <32%'''

#** '''Causes of asthenospermia[https://www.pulsus.com/scholarly-articles/evaluation-and-treatment-of-oligoasthenospermia-in-the-era-of-assisted-reproductive-techniques.html §]'''

#**# '''Sperm structural defects'''

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#*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)'''

#**'''A low volume~~, acidic~~ pH, azoospermic ejaculate can be indicative of obstruction in the genital tract.'''

#**'''If low volume with'''

#***'''Acidic pH, azoospermic ejaculate can be indicative of obstruction in the genital tract'''

#***'''Normal pH (>7.2), azoospermic ejaculate can be indicative of incomplete collection, retrograde ejaculation, or partial obstruction'''

* '''The presence of abnormal semen parameters suggests the presence of a male factor in an infertile couple which should prompt further evaluation of the male'''

==== Secondary ~~semen analyses~~ ====

==== Secondary Semen Analyses ====

* '''DNA fragmentation~~'''~~

** Negatively associated with pregnancy rates and positively associated with miscarriages

===== DNA fragmentation =====

***Patients with high sperm DNA fragmentation can be counseled that there is a possible association with infertility and compromised outcome after ART

* Negatively associated with pregnancy rates and positively associated with miscarriages

**'''Direct measures of sperm DNA fragmentation include (2):'''

**Patients with high sperm DNA fragmentation can be counseled that there is a possible association with infertility and compromised outcome after ART

***Terminal deoxynucleotidyl transferase dUTP nick end labeling '''(TUNEL) assay'''

*'''Direct measures of sperm DNA fragmentation include (2):'''

***'''Comet assay'''

**Terminal deoxynucleotidyl transferase dUTP nick end labeling '''(TUNEL) assay'''

** '''Indications'''

**'''Comet assay'''

***'''Not recommended in the initial evaluation of the infertile couple[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

* '''Indications'''

***May be useful in couples undergoing IVF with repeated IVF failure

**'''Not recommended in the initial evaluation of the infertile couple[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

**Management

**May be useful in couples undergoing IVF with repeated IVF failure

***Currently no effective therapy to correct an abnormal DNA fragmentation result

*Management

***If high sperm DNA fragmentation, consider'''[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

**Currently no effective therapy to correct an abnormal DNA fragmentation result

****Using surgically obtained sperm in addition to ICSI

**If high sperm DNA fragmentation, consider'''[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

*****In a prospective cohort study of over 100 couples with high DNA fragmentation, testicular sperm yielded substantially higher live birth rates than ejaculated sperm.[https://pubmed.ncbi.nlm.nih.gov/28865546/]

***Using surgically obtained sperm in addition to ICSI

****Antioxidant administration

****In a prospective cohort study of over 100 couples with high DNA fragmentation, testicular sperm yielded substantially higher live birth rates than ejaculated sperm.[https://pubmed.ncbi.nlm.nih.gov/28865546/]

****Varicocele repair

***Antioxidant administration

****Frequent ejaculation

***Varicocele repair

*****Decreased abstinence may be an intervention to limit sperm DNA damage.[https://pubmed.ncbi.nlm.nih.gov/29043697/]

***Frequent ejaculation

****Donor sperm

****Decreased abstinence may be an intervention to limit sperm DNA damage.[https://pubmed.ncbi.nlm.nih.gov/29043697/]

*'''Semen WBC staining'''

***Donor sperm

**'''Increased levels of round cells in the semen may result from'''

**#'''Presence of elevated levels of white blood cells in the semen (pyospermia)'''

===== Semen WBC staining =====

**#*White blood cells in the semen may result from infection or inflammation in the proximal or distal male genital tract.

*'''Increased levels of round cells in the semen may result from'''

**#'''Spermatogenic problem where immature germ cells''' (spermatocytes and/or round spermatids) '''are present in the ejaculate'''

*#'''Presence of elevated levels of white blood cells in the semen (pyospermia)'''

**#*No evidence that elevated levels of immature sperm in the semen is deleterious to fertility, and they may be present in semen of infertile men and fertile men with high sperm counts.

*#*White blood cells in the semen may result from infection or inflammation in the proximal or distal male genital tract.

**#'''Idiopathic'''

*#'''Spermatogenic problem where immature germ cells''' (spermatocytes and/or round spermatids) '''are present in the ejaculate'''

**#*Most common cause

*#*No evidence that elevated levels of immature sperm in the semen is deleterious to fertility, and they may be present in semen of infertile men and fertile men with high sperm counts.

**'''Important to know whether men with elevated levels of round cells in the semen have immature germ cells or an infectious or inflammatory etiology for subsequent management (see below)'''

*#'''Idiopathic'''

**'''Leukocytes and immature germ cells are not differentiable with light microscopy'''

*#*Most common cause

***'''Papanicolaou staining may be used'''

*'''Important to know whether men with elevated levels of round cells in the semen have immature germ cells or an infectious or inflammatory etiology for subsequent management (see below)'''

****Immunocytochemical staining provides more information to aid in distinguishing between inflammation and those subtypes involved in fighting off infection

*'''Leukocytes and immature germ cells are not differentiable with light microscopy'''

**'''Indications[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

**'''Papanicolaou staining may be used'''

***'''Increased round cells on semen analysis (>1million/mL)'''

***Immunocytochemical staining provides more information to aid in distinguishing between inflammation and those subtypes involved in fighting off infection

****'''Upper limit of normal as <1 million white blood cells/mL of semen'''

*'''Indications[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

**'''Management'''

**'''Increased round cells on semen analysis (>1million/mL)'''

***'''If staining suggestive of'''

***'''Upper limit of normal as <1 million white blood cells/mL of semen'''

****'''Pyospermia, evaluate for the presence of infection[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

*'''Management'''

*****'''Sexual transmitted infections can also lead to leukocytes in semen and this needs to be ruled-out'''

**'''If staining suggestive of'''

*****'''Chronic prostatitis due to bacterial infection may require long courses of antibiotic treatment''', and some cases of elevated levels of white blood cells may result from chronic nonbacterial prostatitis.

***'''Pyospermia, evaluate for the presence of infection[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

*****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 needs to be ruled-out'''

*****Inflammation may be medically treated with anti-inflammatory drugs.

****'''Chronic prostatitis due to bacterial infection may require long courses of antibiotic treatment''', and some cases of elevated levels of white blood cells may result from chronic nonbacterial prostatitis.

****'''Immature germ cells is a condition that cannot be treated'''

****Leukocytes can occur with UTIs, but unless urine is in the semen, this is an unlikely source.

*'''Anti-sperm antibodies~~'''~~

****Inflammation may be medically treated with anti-inflammatory drugs.

** '''Can result in sperm agglutination in the semen'''

***'''Immature germ cells is a condition that cannot be treated'''

***Anti-sperm antibodies may be present without sperm agglutination and, conversely, agglutination may be present due to other factors, such as the presence of E.coli in the semen

** '''Can impair sperm-ova penetration'''

===== Anti-sperm antibodies =====

**'''Associated with events such as trauma, mumps orchitis, testis malignancy, vasal obstruction, vasectomy that disrupts the blood-testis barrier, or the patency of the male genital tract allowing sperm antigens or genital tract infections to generate anti-sperm antibodies.'''

* '''Can result in sperm agglutination in the semen'''

*** Vasectomy disrupts the blood-testis barrier, resulting in detectable levels of serum antisperm antibodies in 60% to 80% of men.

**Anti-sperm antibodies may be present without sperm agglutination and, conversely, agglutination may be present due to other factors, such as the presence of E.coli in the semen

** IgA and IgG antibodies are the predominant antibodies found in semen, while IgM is rarely found[https://pubmed.ncbi.nlm.nih.gov/33295257/]

* '''Can impair sperm-ova penetration'''

**Tests used (2):

*'''Associated with events such as trauma, mumps orchitis, testis malignancy, vasal obstruction, vasectomy that disrupts the blood-testis barrier, or the patency of the male genital tract allowing sperm antigens or genital tract infections to generate anti-sperm antibodies.'''

***Mixed antiglobulin reaction test

** Vasectomy disrupts the blood-testis barrier, resulting in detectable levels of serum antisperm antibodies in 60% to 80% of men.

***Immunobead (IB) test

* IgA and IgG antibodies are the predominant antibodies found in semen, while IgM is rarely found[https://pubmed.ncbi.nlm.nih.gov/33295257/]

****Gives information about the type and presence of the immunoglobulins and their localization specifically on the sperm head, midpiece or tail or covering the entire sperm

*Tests used (2):

**'''Indications'''

**Mixed antiglobulin reaction test

***'''Should not be done in the initial evaluation of male infertility'''

**Immunobead (IB) test

***'''Should only be considered if it will affect management of the patient.'''

***Gives information about the type and presence of the immunoglobulins and their localization specifically on the sperm head, midpiece or tail or covering the entire sperm

****'''For couples planning on ICSI, ASA testing should not be performed since it will not change management.'''

*'''Indications'''

**'''Management'''

**'''Should not be done in the initial evaluation of male infertility'''

***'''IUI after specific semen processing or ICSI'''

**'''Should only be considered if it will affect management of the patient.'''

****Some have reported improved IUI pregnancy rates with specific semen processing protocols for couples with anti-sperm antibodies compared to standard sperm washing, although the data are limited

***'''For couples planning on ICSI, ASA testing should not be performed since it will not change management.'''

****In those with anti-sperm antibodies, ICSI yields higher pregnancy rates per cycle than IUI with semen processing designed to disrupt the bound antibodies.

*'''Management'''

* '''Sperm aneuploidy testing~~'''~~

**'''IUI after specific semen processing or ICSI'''

**Involves the use of fluorescent molecular probes for chromosomes 13, 18, 21, X, Y because the presence of an extra chromosome for these specific chromosomes is consistent with a potentially viable but affected offspring. Aneuploidy of all other human chromosomes is not consistent with a viable offspring.[https://pubmed.ncbi.nlm.nih.gov/33295257/]

***Some have reported improved IUI pregnancy rates with specific semen processing protocols for couples with anti-sperm antibodies compared to standard sperm washing, although the data are limited

**'''Indications'''

***In those with anti-sperm antibodies, ICSI yields higher pregnancy rates per cycle than IUI with semen processing designed to disrupt the bound antibodies.

***'''Recurrent pregnancy loss'''

*'''Sperm penetration assay~~''' most~~ closely models incubational in vitro fertilization

===== Sperm aneuploidy testing =====

* '''~~Sperm culture: limited~~ seminal concentrations of the majority of bacteria including E. Coli have minimal or no effects on sperm motility in vivo'''

*Involves the use of fluorescent molecular probes for chromosomes 13, 18, 21, X, Y because the presence of an extra chromosome for these specific chromosomes is consistent with a potentially viable but affected offspring. Aneuploidy of all other human chromosomes is not consistent with a viable offspring.[https://pubmed.ncbi.nlm.nih.gov/33295257/]

*'''Indications'''

**'''Recurrent pregnancy loss'''

===== 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'''

===== Fructose =====

*'''Produced in the male reproductive tract by the seminal vesicles and is released into the semen during ejaculation'''

*Energy source for spermatozoa[https://pubmed.ncbi.nlm.nih.gov/11554980/ §]

*Mean concentration of fructose in human semen is 2–3 mg/mL (11–16 μmol/mL)[https://pubmed.ncbi.nlm.nih.gov/11554980/ §]

**'''Low semen fructose may suggest ejaculatory duct obstruction'''

=== Serum ===

==== FSH and Total ~~testosterone~~ ====

==== FSH and Morning Total Testosterone ====

*'''Not recommended as a primary first-line test in the evaluation of male infertility[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

*'''Indications (6):[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

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===== FSH =====

* '''Indirect assessment of germ cell mass'''

** '''If ~~reduced~~ testicle ~~size~~ and FSH >7.6 IU/L --> consider spermatogenic dysfunction'''

** '''If testicle long axis < 4.6 cm and FSH >7.6 IU/L --> consider spermatogenic dysfunction'''

**'''If ~~normal~~ testicle ~~size~~ and FSH <7.6 IU/L --> consider obstructive azoospermia'''

**'''If testicle long axis > 4.6 cm and FSH < 7.6 IU/L --> consider obstructive azoospermia'''

===== Total ~~testosterone~~ =====

===== Morning Total Testosterone =====

*'''Should be defined based upon a morning blood sample,''' since levels drop during the day

*'''≥300 ng/dL considered adequate (164 ng/dL bioavailable)'''

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*#'''LH'''

*#'''Estradiol'''

*#'''Prolactin ~~levels~~'''

*#'''Prolactin'''

*#*The relationship of testosterone, LH, FSH, and prolactin helps to identify the clinical condition.

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=== Post-ejaculate Urine Analysis ===

* Used to diagnose retrograde ejaculation

* '''Used to diagnose retrograde ejaculation'''

* Viable sperm from urine or any location within the male reproductive tract can be used with ART to achieve a pregnancy.

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* '''Karyotype and Y chromosome microdeletion'''

**'''Primary infertility and ~~azoospermia or severe oligozoospermia (<5 million sperm/mL) with~~ (3):'''

**'''Primary infertility and (3):'''

**# '''~~Elevated~~ FSH OR'''

**#'''Azoospermia or severe oligozoospermia (<5 million sperm/mL) with elevated FSH OR'''

**# '''Testicular atrophy OR'''

**#'''Testicular atrophy OR'''

**# '''Presumed diagnosis of impaired sperm production as the cause of azoospermia'''

**#'''Presumed diagnosis of impaired sperm production as the cause of azoospermia'''

*'''Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation carrier testing (3):'''

*#'''Vasal agenesis/abnormalities'''

*#'''Vasal agenesis/abnormalities OR'''

*#'''Idiopathic obstructive azoospermia'''

*#'''Idiopathic obstructive azoospermia OR'''

*#'''If the female partner is a carrier (to consider for preimplantation diagnosis)'''

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=== Renal ultrasound ===

*'''Goal is to identify potential associated renal abnormalities.'''

**The male genital tract is derived from the Wolffian or mesonephric tract. It is a paired organ, which forms the epididymis, vas deferens, and seminal vesicles during embryogenesis. As it connects to the primitive kidney, abnormalities in the Wolffian duct can lead to renal anomalies.

**'''The male genital tract is derived from the Wolffian or mesonephric tract.''' It is a paired organ, which forms the epididymis, vas deferens, and seminal vesicles during embryogenesis. '''As it connects to the primitive kidney, abnormalities in the Wolffian duct can lead to renal anomalies.'''

*'''Indications (2):'''

*'''Indications (1):'''

*#'''Congenital absence of the vas(a) (regardless of the CFTR status)'''

*#*≈26-75% of ~~men~~ with unilateral absence of the vas deferens will have ipsilateral renal anomalies including agenesis.

*#*≈26-75% of males with unilateral absence of the vas deferens will have ipsilateral renal anomalies including agenesis.

*#*≈10% of ~~men~~ with bilateral vasal agenesis will have ipsilateral renal anomalies including agenesis.

*#*≈10% of males with bilateral vasal agenesis will have ipsilateral renal anomalies including agenesis.

*#'''Patient with CFTR'''

*#*Even in men with CBAVD and CFTR mutations, unilateral renal agenesis may occur

=== Trans-rectal Ultrasound (TRUS) ===

*Used to ~~assess~~ the anatomy of the primary organs/structures involved in ejaculation including the prostate, seminal vesicles, vasal ampulla, and ejaculatory ducts

*Used to

**Assess the anatomy of the primary organs/structures involved in ejaculation including the prostate, seminal vesicles, vasal ampulla, and ejaculatory ducts

**Rule out ejaculatory duct obstruction

*'''Should not be performed as part of the initial evaluation'''

*'''Indications[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

*#'''Semen analysis suggestive of ejaculatory dust obstruction (2):'''

*#*'''Low semen volume with'''

*#*'''Low semen volume with azoospermia and palpable vasa'''

*#**'''~~Azoospermia~~ and ~~palpable vasa~~'''

*#*'''Low semen volume and significant asthenospermia (total motility <40% or progressive motility <32%)'''

*#**'''~~Significant asthenospermia'''~~

*#**'''Normal semen is derived from testicular (~10%), prostatic (~20%), and seminal vesicle (~70%) fluid.'''

*#***'''Normal semen is derived from testicular (~10%), prostatic (~20%), and seminal vesicle (~70%) fluid.'''

*#***All components are androgen sensitive so that men with testosterone deficiency may have low semen volume and the utility of TRUS in such circumstances may be low.

*#***'''Seminal vesicle fluid is alkaline. Obstruction that limits or prevents the seminal vesicle contribution will lead to acidic semen (pH <7.0)'''.

*#***'''Seminal vesicle fluid is alkaline. Obstruction that limits or prevents the seminal vesicle contribution will lead to acidic semen (pH <7.0)'''.

*#****Men with a normal semen pH are unlikely to have a complete distal genital tract obstruction.

*#'''Symptoms (e.g., painful ejaculation)'''

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**'''Should not be routinely performed in the initial evaluation of the infertile male.'''

***'''Routine use of ultrasonography to investigate presumed varicocele is to be discouraged''', as treatment of non-palpable varicoceles is not associated with improved semen parameters and fertility rates as has been shown for treatment of clinical varicoceles.

**'''May be used to if difficult to examine scrotum (obese patient or when the dartos muscle remains highly contracted during the physical exam)'''

**'''May be used if difficult to examine scrotum (obese patient or when the dartos muscle remains highly contracted during the physical exam)'''

=== Abdominal imaging for isolated right varicocele ===

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== Testicular biopsy ==

* '''Should not routinely be performed to differentiate between obstructive azoospermia and non-obstructive azoospermia[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

**Differentiation of obstructive azoospermia from non-obstructive azoospermia may most frequently be predicted from clinical and laboratory results without the need for surgical diagnostic biopsy.

**'''Differentiation of obstructive azoospermia from non-obstructive azoospermia may most frequently be predicted from clinical and laboratory results without the need for surgical diagnostic biopsy.'''

***FSH ~~levels greater than~~ 7.6 IU/L and testis longitudinal axis ~~less than~~ 4.6 cm indicate an 89% likelihood of spermatogenic dysfunction as the etiology

***'''FSH > 7.6 IU/L and testis longitudinal axis < 4.6 cm indicate an 89% likelihood of spermatogenic dysfunction as the etiology'''

***FSH ~~levels less than~~ 7.6 IU/L and testis longitudinal axes ~~greater than~~ 4.6 cm indicate 96% likelihood of obstruction as the etiology

***'''FSH < 7.6 IU/L and testis longitudinal axes > 4.6 cm indicate 96% likelihood of obstruction as the etiology'''

**In the infrequent cases with intermediate values, testis biopsy may be performed

**'''In the infrequent cases with intermediate values, testis biopsy may be performed'''

***'''Consider diagnostic and therapeutic biopsy if FSH and testicular volume normal but no clinical evidence of obstruction'''

****May identify germ cell maturation arrest

***In the rare cases where testis biopsy is done primarily for diagnostic purposes, sperm cryopreservation from the sample should be attempted if ART is an option.

* Spermatogenesis may be highly focal in men with azoospermia so a random biopsy may miss areas of sperm production

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== Special Scenarios ==

===Recurrent pregnancy loss===

*Defined as ~~two or more~~ failed pregnancies

*'''Defined as ≥2 failed pregnancies'''

**Distinct from infertility

* Most miscarriages are related to abnormalities within the fetus itself[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]

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*#'''Hematologic and immunologic disorders of the female partner'''

*#'''Female partner endocrine issues (e.g., thyroid and diabetes)'''

*#'''Male factor issues'''*#*'''Most common identified etiologic issues in males: karyotypic abnormalities and sperm DNA fragmentation.'''

*#'''Male factor issues'''

*#*'''Most common identified etiologic issues in males: karyotypic abnormalities and sperm DNA fragmentation.'''

*'''Diagnosis and Evaluation (3):'''

*#'''Karyotype'''

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* '''Prior to commencement of gonadotoxic therapies and other cancer treatments, discuss the effects of therapy on sperm production with patients[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

**Radiotherapy and chemotherapy used for cancer and other medical conditions can ~~often~~ lead to temporary or ~~even~~ long-term gonadal injury ~~in men~~.

**Radiotherapy and chemotherapy used for cancer and other medical conditions can lead to temporary or long-term gonadal injury.

***The recovery of sperm production following radiotherapy and/or chemotherapy depends on the survival of spermatogonial stem cells in the testis.

****The recovery of sperm in the ejaculate may take months to years when ~~the~~ radiation dose ~~exceeds~~ 1 Gy; a dose ~~exceeding~~ 10 Gy will often result in permanent azoospermia

****Radiation

****Fractionated radiation (given over the course of weeks) may have a more detrimental effect on spermatogenesis than a single radiation dose

*****The recovery of sperm in the ejaculate may take months to years when radiation dose > 1 Gy; dose > 10 Gy will often result in permanent azoospermia

****Alkylating agents (e.g., procarbazine, cyclophosphamide, ifosfamide) and cisplatin target spermatogonial stem cells, and these drugs are the most likely to lead to permanent azoospermia at high doses

*****Fractionated radiation (given over the course of weeks) may have a more detrimental effect on spermatogenesis than a single radiation dose

****Most other chemotherapeutic agents (e.g., anthracyclines, microtubule inhibitors, antimetabolites, topoisomerase inhibitors) target differentiating germ cells in the testis (e.g., spermatids, spermatocytes, differentiating spermatogonia) and cause a transient reduction in sperm parameters with gradual recovery of sperm count observed three to six months after cessation of therapy.

****Chemotherapy

*****Topoisomerase II inhibitors (e.g., etoposide) are most toxic to spermatocytes with little to no toxicity to stem cells

*****Alkylating agents (e.g., procarbazine, cyclophosphamide, ifosfamide) and cisplatin target spermatogonial stem cells, and these drugs are the most likely to lead to permanent azoospermia at high doses

*****Doxorobucin targets differentiating spermatogonia and spermatocytes

*****Most other chemotherapeutic agents (e.g., anthracyclines, microtubule inhibitors, antimetabolites, topoisomerase inhibitors) target differentiating germ cells in the testis (e.g., spermatids, spermatocytes, differentiating spermatogonia) and cause a transient reduction in sperm parameters with gradual recovery of sperm count observed three to six months after cessation of therapy.

* Encourage ~~men to bank~~ sperm, preferably multiple specimens when possible, prior to commencement of gonadotoxic therapy or other cancer treatment that may affect fertility ~~in men.~~[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]

******Topoisomerase II inhibitors (e.g., etoposide) are most toxic to spermatocytes with little to no toxicity to stem cells

******Doxorobucin targets differentiating spermatogonia and spermatocytes

* '''Encourage sperm banking, preferably multiple specimens when possible, prior to commencement of gonadotoxic therapy or other cancer treatment that may affect fertility[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

**Couple may need to undergo several cycles of IVF treatment in order to achieve a pregnancy

**~~Men presenting~~ with cancer will generally have poorer semen parameters than normal donors, and their sperm respond less favorably to freeze-thawing (with poorer post-thaw motility) than donor sperm

**Malespresenting with cancer will generally have poorer semen parameters than normal donors, and their sperm respond less favorably to freeze-thawing (with poorer post-thaw motility) than donor sperm

*For azoospermic men with an intratesticular lesion, cryopreservation of testicular tissue should be considered during orchiectomy or excisional biopsy of the testicular lesion (an Onco-TESE approach)

*'''For azoospermic men with an intratesticular lesion, cryopreservation of testicular tissue should be considered during orchiectomy or excisional biopsy of the testicular lesion (an Onco-TESE approach)'''

*'''Inform patients undergoing a retroperitoneal lymph node dissection (RPLND) of the risk of aspermia and the availability of sperm banking prior to surgery.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

**'''Obtain a post-orgasmic urinalysis for men with aspermia after RPLND who are interested in fertility.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

***Given the distribution of the nodes involved in drainage of the testes, the lumbar sympathetic nerve fibers responsible for ejaculation (T10-L2) are in close proximity to the node dissection templates.

***'''Sympathetic nerve fiber damage, such as that which can occur during a RPLND, can result in failure of the bladder neck to contract effectively allowing semen deposited into the prostatic urethra to pass in a retrograde fashion into the bladder (i.e., RE).[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]'''

***As with any neural trauma, maximum recovery can take 12 to 24 months and thus, patients who have had nerve sparing RPLND should be told that return of antegrade ejaculation may take a protracted period of time. If aspermia remains 24 months after RPLND, then the patient should be informed that this is likely to be permanent.

***'''As with any neural trauma, maximum recovery can take 12 to 24 months and thus, patients who have had nerve sparing RPLND should be told that return of antegrade ejaculation may take a protracted period of time.'''

****If aspermia remains 24 months after RPLND, then the patient should be informed that this is likely to be permanent.

* '''Inform patients undergoing chemotherapy and/or radiation therapy to avoid pregnancy for a period of at least 12 months after completion of treatment.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''

**One of the major concerns regarding the effects of gonadotoxic therapies in ~~men~~ wishing to father children is the induction of mutations in developing testicular germ cells. Studies have clearly demonstrated that radiation and chemotherapy can alter the genomic integrity of testicular germ cells.

**One of the major concerns regarding the effects of gonadotoxic therapies in males wishing to father children is the induction of mutations in developing testicular germ cells.

***The genomic damage induced by these treatments is germ cell stage specific.

***Studies have clearly demonstrated that radiation and chemotherapy can alter the genomic integrity of testicular germ cells.

**This implies that during and for a defined period of time after exposure to radiation and/or chemotherapy (depending on the susceptible germ cell) a ~~man~~ can produce an increased proportion of genetically abnormal spermatozoa. Conceiving a child during this period can substantially increase the risk of genetic mutations in the offspring.

****The genomic damage induced by these treatments is germ cell stage specific.

****This implies that during and for a defined period of time after exposure to radiation and/or chemotherapy (depending on the susceptible germ cell) a male can produce an increased proportion of genetically abnormal spermatozoa. Conceiving a child during this period can substantially increase the risk of genetic mutations in the offspring.

*Consider informing patients that a SA performed after gonadotoxic therapies, should be done at least 12 months (and preferably 24 months) after treatment completion.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]

**Studies demonstrate lowest sperm concentration by 12 months and maximization of recovery in the majority of studies between 2 to 3 years after the completion of treatment[https://pubmed.ncbi.nlm.nih.gov/33295257/]

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# List 6 causes of low-volume semen.

#What are the genetic tests in infertility? When are they indicated?

== Mock Oral Exam ==

* [https://www.youtube.com/watch?v=HXdKUcrJUac Azoozpermia] (Master the Medicine)

*[https://www.youtube.com/watch?v=6gg9J-B-f8E Ejaculatory Duct Obstruction] (Master the Medicine)

*[https://www.youtube.com/watch?v=USSSRzA2A80 Vasectomy] (Master the Medicine)

*[https://www.youtube.com/watch?v=33Qopru4An8 Vasectomy Reversal and ART] (Master the Medicine)

*[https://www.youtube.com/watch?v=EKZAXemK7-A Infertility] (Master the Medicine)

== Next Chapter: [[Infertility: Management|Management of Infertility]] ==

@@ Line 3: / Line 3: @@
 * '''See [https://www.auanet.org/documents/Guidelines/PDF/Male-Infertility-Algorithm.pdf Algorithm from Original Guidelines]'''
+*See [https://www.youtube.com/watch?v=6d0TZRTQLJ8 Video Reviewing Guidelines] (Dr. Joshua Helpern)
 '''See 2015 CUA Azoospermia Guideline Notes'''
@@ Line 59: / Line 60: @@
 * '''<span style="color:#ff0000">Labs</span>'''
 ** '''<span style="color:#ff0000">Semen analysis</span>'''
-*** '''<span style="color:#ff0000">At least two SAs obtained a month apart are important to consider, especially if the first SA has abnormal parameters</span>'''
+*** '''<span style="color:#ff0000">At least two SAs obtained a month apart are important to consider, especially if the first SA has abnormal parameters[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]</span>'''
 ****'''Semen parameters are highly variable biological measures and may vary substantially from test to test'''
 ****'''Up to 35% of men with non-obstructive azoospermia will have sperm detected on subsequent SA without medical intervention[https://pubmed.ncbi.nlm.nih.gov/9222005/]'''
@@ Line 70: / Line 71: @@
 ***#'''<span style="color:#ff0000">Atrophic testes</span>'''
 ***#'''<span style="color:#ff0000">Evidence of hormonal abnormality on physical evaluation</span>'''
-****'''<span style="color:#ff0000">If testosterone low (<300ng/mL), get (3)</span>'''
+****'''<span style="color:#ff0000">If testosterone low (<300ng/mL), get (5)</span>'''
 ****#'''<span style="color:#ff0000">Repeat measurement of total testosterone (or bioavailable testosterone)</span>'''
 ****#'''<span style="color:#ff0000">Free (or bioavailable) testosterone</span>'''
@@ Line 77: / Line 78: @@
 ****#'''<span style="color:#ff0000">Prolactin levels</span>'''
 **'''<span style="color:#ff0000">Genetic testing, if indicated (see below)</span>'''
-***'''<span style="color:#ff0000">Karyotype and Y</span><span style="color:#ff0000">-microsome deletion</span><span style="color:#ff0000">, if (</span><span style="color:#ff0000">3</span><span style="color:#ff0000">):</span>'''
+***'''<span style="color:#ff0000">Karyotype and Y</span><span style="color:#ff0000">-microsome deletion</span><span style="color:#ff0000">, if</span>'''
-***#'''<span style="color:#ff0000">Azoospermia or severe oligozoospermia (<5 million sperm/mL) with elevated FSH</span>'''
+****'''<span style="color:#ff0000">Primary infertility and (</span><span style="color:#ff0000">3</span><span style="color:#ff0000">):</span>'''
-***#'''<span style="color:#ff0000">Testicular atrophy</span>'''
+****#'''<span style="color:#ff0000">Azoospermia or severe oligozoospermia (<5 million sperm/mL) with elevated FSH OR</span>'''
-***#'''<span style="color:#ff0000">Presumed diagnosis of impaired sperm production as the cause of azoospermia</span>'''
+****#'''<span style="color:#ff0000">Testicular atrophy OR</span>'''
-***'''<span style="color:#ff0000">Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation carrier testing (including assessment of the 5T allele), if (2):</span>'''
+****#'''<span style="color:#ff0000">Presumed diagnosis of impaired sperm production as the cause of azoospermia</span>'''
+***'''<span style="color:#ff0000">Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation carrier testing (including assessment of the 5T allele), if (3):</span>'''
 ***#'''<span style="color:#ff0000">Vasal agenesis (unilateral or bilateral)</span>'''
 ***#'''<span style="color:#ff0000">Idiopathic obstructive azoospermia</span>'''
+***#'''<span style="color:#ff0000">If the female partner is a carrier (to consider for preimplantation diagnosis)</span>'''
 *'''<span style="color:#ff0000">Imaging</span>'''
-**'''<span style="color:#ff0000">Renal ultrasound, if vasal agenesis</span>'''
+**'''<span style="color:#ff0000">Renal ultrasound, if (1):</span>'''
-**'''<span style="color:#ff0000">Trans-rectal ultrasound, if</span>'''
+**#'''<span style="color:#ff0000">Vasal agenesis</span>'''
-**#'''<span style="color:#ff0000">Low volume azoospermia or significant asthenospermia</span>'''
+**'''<span style="color:#ff0000">Trans-rectal ultrasound, if (3):</span>'''
+**#'''<span style="color:#ff0000">Low semen volume with azoospermia and palpable vasa OR</span>'''
+**#'''<span style="color:#ff0000">Low semen volume and significant asthenospermia (total motility <40% or progressive motility <32%) OR</span>'''
 **#'''<span style="color:#ff0000">Symptoms (e.g. painful ejaculation)</span>'''
@@ Line 137: / Line 142: @@
 *** '''Penile plaque''' as in Peyronie’s disease may make it difficult for vaginal intercourse
 *** '''Penile lesions/ulcers/discharge''' may be a sign of sexually transmitted infection
-**'''<span style="color:#ff0000">Scrotum'''
+**'''<span style="color:#ff0000">Scrotum (5)'''
-*** '''Scars''' suggest previous scrotal surgery/trauma
+**# '''Scars''' suggest previous scrotal surgery/trauma
-***'''<span style="color:#ff0000">Testis'''
+**#'''<span style="color:#ff0000">Testis'''
-****'''<span style="color:#ff0000">Size and consistency of the testis; size correlates well with sperm production'''
+**#*'''<span style="color:#ff0000">Size and consistency of the testis; size correlates well with sperm production'''
-***** '''<span style="color:#ff0000">Long axis length <4.6cm associated with impaired spermatogenesis</span>'''
+**#** '''<span style="color:#ff0000">Long axis length <4.6cm associated with impaired spermatogenesis</span>'''
-***** '''<span style="color:#ff0000">Volume <20mL considered low</span>'''
+**#** '''<span style="color:#ff0000">Volume <20mL considered low</span>'''
-*****Obstructive azoospermia is suspected if the physical examination reveals testes of normal size, fully descended into the scrotum and bilaterally indurated epididymides with or without absence of the vas deferens
+**#**Obstructive azoospermia is suspected if the physical examination reveals testes of normal size, fully descended into the scrotum and bilaterally indurated epididymides with or without absence of the vas deferens
-*****'''When the testes are atrophied and soft, especially in the presence of FSH greater than 7.6 IU/L, the results are suggestive of spermatogenic failure rather than obstructive azoospermia.'''
+**#**'''When the testes are atrophied and soft, especially in the presence of FSH greater than 7.6 IU/L, the results are suggestive of spermatogenic failure rather than obstructive azoospermia.'''
-**** Location as scrotal position of the testes is important for normal function
+**#* Location as scrotal position of the testes is important for normal function
-**** Exam may also reveal masses consistent with a testicular cancer
+**#* Exam may also reveal masses consistent with a testicular cancer
-*** '''<span style="color:#ff0000">Epididymides'''
+**# '''<span style="color:#ff0000">Vas deferens'''
-**** Shape/consistency as normal development should be identified to determine atresia that could be identified by the presence of a ''CFTR'' mutation.
+**#* Shape/consistency as normal development and contour should be confirmed to rule out agenesis as may be seen in the presence of a ''CFTR'' mutation or aberrant Wolffian duct embryogenesis
-**** Induration/dilation could suggest obstruction.
+**#**'''<span style="color:#ff0000">Unilateral absence</span>'''
-**** Epididymal cysts or spermatoceles may also lead to obstruction.
+**#*** '''<span style="color:#ff0000">Suggests complete lack of Wolffian duct development on that side, including renal agenesis</span>'''
-*** '''<span style="color:#ff0000">Vas deferens'''
+**#**** '''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'''
-**** Shape/consistency as normal development and contour should be confirmed to rule out agenesis as may be seen in the presence of a ''CFTR'' mutation or aberrant Wolffian duct embryogenesis
+**#**** '''Recall, male structures derived from Wolffian ducts:'''
-*****'''<span style="color:#ff0000">Unilateral absence</span>'''
+**#****# '''Body and tail of epididymis (note efferent ductules and head of epididymis from mesonephric tubules)'''
-****** '''<span style="color:#ff0000">Suggests complete lack of Wolffian duct development on that side, including renal agenesis</span>'''
+**#****# '''Vas deferens'''
-******* '''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'''
+**#****# '''Seminal vesicles'''
-******* '''Recall, male structures derived from Wolffian ducts:'''
+**#****#* Distally, the wolffian ducts join the urogenital sinus by about 30 days gestation, where they develop into the seminal vesicles
-*******# '''Body and tail of epididymis (note efferent ductules and head of epididymis from mesonephric tubules)'''
+**#****# '''Ejaculatory duct'''
-*******# '''Vas deferens'''
+**#****# '''Appendix epididymis'''
-*******# '''Seminal vesicles'''
+**#**** '''Male structures derived from Müllerian duct (2):'''
-*******#* Distally, the wolffian ducts join the urogenital sinus by about 30 days gestation, where they develop into the seminal vesicles
+**#****#'''Appendix testis'''
-*******# '''Ejaculatory duct'''
+**#****#'''Prostatic utricle'''
-*******# '''Appendix epididymis'''
+**#**** '''Male structures derived from urogenital sinus:'''
-******* '''Male structures derived from Müllerian duct (2):'''
+**#****# '''Prostate'''
-*******#'''Appendix testis'''
+**#****# '''Bulbourethral glands'''
-*******#'''Prostatic utricle'''
+**#** '''<span style="color:#ff0000">Bilateral absence</span>'''
-******* '''Male structures derived from urogenital sinus:'''
+**#*** '''<span style="color:#ff0000">Consider investigation for CF gene mutation</span>'''
-*******# '''Prostate'''
+**#**** '''Mutations in the ''CFTR'' gene are present in up to 80% of men with congenital bilateral absence of the vas deferens (CBAVD), 20% of men with''' '''congenital''' '''unilateral absence of the vas deferens''' and 21% of men with idiopathic epididymal obstruction[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]
-*******# '''Bulbourethral glands'''
+**#***** Most common CFTR mutation is ΔF508, which is severe
-***** '''<span style="color:#ff0000">Bilateral absence</span>'''
+**#***** ≈7% of brothers of patients with CBAVD will have also vasal agenesis
-****** '''<span style="color:#ff0000">Consider investigation for CF gene mutation</span>'''
+**#***** No association between CBAVD and Y microdeletions.
-******* '''Mutations in the ''CFTR'' gene are present in up to 80% of men with congenital bilateral absence of the vas deferens (CBAVD), 20% of men with''' '''congenital''' '''unilateral absence of the vas deferens''' and 21% of men with idiopathic epididymal obstruction[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]
+**#**** '''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).'''
-******** Most common CFTR mutation is ΔF508, which is severe
+**#***** '''Only a portion of CFTR mutations are detected by routine testing.'''
-******** ≈7% of brothers of patients with CBAVD will have also vasal agenesis
+**#****** '''A male with CBAVD should be assumed 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.'''
-******** No association between CBAVD and Y microdeletions.
+**#*** '''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 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).'''
+**#** '''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'''
-******** '''Only a portion of CFTR mutations are detected by routine testing.'''
+**#*** '''26% of males with unilateral congenital absence of the vas deferens and 11% of males with CBAVD had an absent ipsilateral kidney''';
-********* '''A male with CBAVD should be assumed 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.'''
+**#**** Most of the bilateral CAVD patients with an absent ipsilateral kidney are in patients with no identifiable CF gene mutation.
-****** '''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'''
+**#* Presence/location of any vasectomy defect or granuloma should also be assessed
-***** '''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'''
+**#'''<span style="color:#ff0000">Epididymides'''
-****** '''26% of males with unilateral congenital absence of the vas deferens and 11% of males with CBAVD had an absent ipsilateral kidney''';
+**#* Shape/consistency as normal development should be identified to determine atresia that could be identified by the presence of a ''CFTR'' mutation.
-******* Most of the bilateral CAVD patients with an absent ipsilateral kidney are in patients with no identifiable CF gene mutation.
+**#* Induration/dilation could suggest obstruction.
-**** Presence/location of any vasectomy defect or granuloma should also be assessed
+**#* Epididymal cysts or spermatoceles may also lead to obstruction.
-***'''<span style="color:#ff0000">Varicoceles'''
+**#'''<span style="color:#ff0000">Varicoceles'''
-**** Large varicoceles are associated with greater preoperative impairment in semen quality than small varicoceles
+**#* Potential mechanisms of varicocele contributing to infertility
-**** Varicocele treatment may be more cost effective than assisted-reproductive therapy or can lower the intensity of treatment'''§'''
+**#**Hyperthermia
-**** '''See [[Varicocele]] Chapter Notes'''
+**#**Testicular hormonal imbalance
+**#**Increased reactive oxygen species
+**#**Hypoperfusion leading to hypoxia
+**#*
+**#*Large varicoceles are associated with greater preoperative impairment in semen quality than small varicoceles
+**#* Varicocele treatment may be more cost effective than assisted-reproductive therapy or can lower the intensity of treatment'''§'''
+**#* '''See [[Varicocele]] Chapter Notes'''
 ** '''<span style="color:#ff0000">Digital rectal exam'''
 *** '''Midline prostatic cysts or dilated seminal vesicles''' may assist in the diagnosis of ejaculatory duct obstruction
@@ Line 199: / Line 210: @@
 **#'''<span style="color:#ff0000">Complete asthenozoospermia</span>'''
 **#'''<span style="color:#ff0000">Some types of teratozoospermia (e.g., complete globozoospermia)</span>'''
+*'''<span style="color:#ff0000">Should be examined under the microscope within one hour of collection</span>'''
+*'''<span style="color:#ff0000">Should be given after 2-3 days of abstinence</span>'''
+*'''<span style="color:#ff0000">Number of samples</span>'''
+**'''<span style="color:#ff0000">At least two semen analyses obtained a month apart are important to consider, especially if the first SA has abnormal parameters[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]</span>'''
+***'''If azoospermia, a second SA should be performed at least one to two weeks later.'''
 ==== <span style="color:#ff0000">WHO semen parameter percentiles</span> ====
 * '''<span style="color:#ff0000">Derived from men whose partners became pregnant (fertile population) within 1 year of discontinuation of contraceptives.</span>'''
-* '''<span style="color:#ff0000">except in cases of azoospermia and some types of teratozoospermia (e.g., complete globozoospermia), necrozoospermia, or complete asthenozoospermia</span>'''
 * '''<span style="color:#ff0000">The 5th percentile is used to describe infertility cut-offs for 7 semen parameters</span>'''
 ** '''Values falling above or below the lower limit do not by themselves predict either fertility or infertility;''' '''males with''' '''abnormal semen parameters have contributed to a prior successful pregnancy through natural conception'''
@@ Line 226: / Line 241: @@
 #*'''<span style="color:#ff0000">If semen analysis shows azoospermia, laboratory should then centrifuge the ejaculate and re-suspend the pellet in a small volume of seminal plasma and examine under wet mount microscopy for the presence of rare sperm.</span>'''
 #**'''If no sperm are present, a second semen analysis should be performed at least one to two weeks later. If the sample is azoospermic, then another pellet analysis should be performed.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
+#**'''Further investigations for azoospermia depend on if it is associated with low-volume (obstructive) azoospermia or normal-volume azoospermia'''
+#*'''Azoospermic patients with[https://pubmed.ncbi.nlm.nih.gov/15363709/ §]'''
+#**'''Normal ejaculate volume may have either obstruction of the reproductive system or abnormalities of spermatogenesis'''
+#**'''Low semen volume and normal sized testes may have ejaculatory dysfunction or ejaculatory duct obstruction'''
 #'''<span style="color:#ff0000">Concentration <15 million/mL</span>'''
 #* Visual assessment under microscopy
@@ Line 232: / Line 251: @@
 #'''<span style="color:#ff0000">Total motility <40%</span>'''
 #* '''Visual assessment under microscopy'''
-#* '''Asthenospermia is when total motility <40% or progressive motility <32%'''
+#* '''<span style="color:#ff0000">Asthenospermia is when total motility <40% or progressive motility <32%'''
 #** '''Causes of asthenospermia[https://www.pulsus.com/scholarly-articles/evaluation-and-treatment-of-oligoasthenospermia-in-the-era-of-assisted-reproductive-techniques.html §]'''
 #**# '''Sperm structural defects'''
@@ Line 266: / Line 285: @@
 #*In spinal cord injury, a brown hue can be noted in the semen
 #*'''<span style="color:#ff0000">pH should be 7.2-7.8 (alkaline due to seminal vesicle contribution)</span>'''
-#**'''<span style="color:#ff0000">A low volume, acidic pH, azoospermic ejaculate can be indicative of obstruction in the genital tract.</span>'''
+#**'''<span style="color:#ff0000">If low volume with</span>'''
+#***'''<span style="color:#ff0000">Acidic pH, azoospermic ejaculate can be indicative of obstruction in the genital tract</span>'''
+#***'''<span style="color:#ff0000">Normal pH (>7.2), azoospermic ejaculate can be indicative of incomplete collection, retrograde ejaculation, or partial obstruction</span>'''
 * '''The presence of abnormal semen parameters suggests the presence of a male factor in an infertile couple which should prompt further evaluation of the male'''
-==== Secondary semen analyses ====
+==== Secondary Semen Analyses ====
-* '''DNA fragmentation'''
-** Negatively associated with pregnancy rates and positively associated with miscarriages
+===== DNA fragmentation =====
-***Patients with high sperm DNA fragmentation can be counseled that there is a possible association with infertility and compromised outcome after ART
+* Negatively associated with pregnancy rates and positively associated with miscarriages
-**'''Direct measures of sperm DNA fragmentation include (2):'''
+**Patients with high sperm DNA fragmentation can be counseled that there is a possible association with infertility and compromised outcome after ART
-***Terminal deoxynucleotidyl transferase dUTP nick end labeling '''(TUNEL) assay'''
+*'''Direct measures of sperm DNA fragmentation include (2):'''
-***'''Comet assay'''
+**Terminal deoxynucleotidyl transferase dUTP nick end labeling '''(TUNEL) assay'''
-** '''<span style="color:#ff0000">Indications</span>'''
+**'''Comet assay'''
-***'''<span style="color:#ff0000">Not recommended in the initial evaluation of the infertile couple</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
+* '''<span style="color:#ff0000">Indications</span>'''
-***May be useful in couples undergoing IVF with repeated IVF failure
+**'''<span style="color:#ff0000">Not recommended in the initial evaluation of the infertile couple</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
-**Management
+**May be useful in couples undergoing IVF with repeated IVF failure
-***Currently no effective therapy to correct an abnormal DNA fragmentation result
+*Management
-***If high sperm DNA fragmentation, consider'''[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
+**Currently no effective therapy to correct an abnormal DNA fragmentation result
-****Using surgically obtained sperm in addition to ICSI
+**If high sperm DNA fragmentation, consider'''[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
-*****In a prospective cohort study of over 100 couples with high DNA fragmentation, testicular sperm yielded substantially higher live birth rates than ejaculated sperm.[https://pubmed.ncbi.nlm.nih.gov/28865546/]
+***Using surgically obtained sperm in addition to ICSI
-****Antioxidant administration
+****In a prospective cohort study of over 100 couples with high DNA fragmentation, testicular sperm yielded substantially higher live birth rates than ejaculated sperm.[https://pubmed.ncbi.nlm.nih.gov/28865546/]
-****Varicocele repair
+***Antioxidant administration
-****Frequent ejaculation
+***Varicocele repair
-*****Decreased abstinence may be an intervention to limit sperm DNA damage.[https://pubmed.ncbi.nlm.nih.gov/29043697/]
+***Frequent ejaculation
-****Donor sperm
+****Decreased abstinence may be an intervention to limit sperm DNA damage.[https://pubmed.ncbi.nlm.nih.gov/29043697/]
-*'''<span style="color:#ff0000">Semen WBC staining</span>'''
+***Donor sperm
-**'''<span style="color:#ff0000">Increased levels of round cells in the semen may result from</span>'''
-**#'''<span style="color:#ff0000">Presence of elevated levels of white blood cells in the semen (pyospermia)</span>'''
+===== <span style="color:#ff0000">Semen WBC staining</span> =====
-**#*White blood cells in the semen may result from infection or inflammation in the proximal or distal male genital tract.
+*'''<span style="color:#ff0000">Increased levels of round cells in the semen may result from</span>'''
-**#'''<span style="color:#ff0000">Spermatogenic problem where immature germ cells</span>''' (spermatocytes and/or round spermatids) '''<span style="color:#ff0000">are present in the ejaculate</span>'''
+*#'''<span style="color:#ff0000">Presence of elevated levels of white blood cells in the semen (pyospermia)</span>'''
-**#*No evidence that elevated levels of immature sperm in the semen is deleterious to fertility, and they may be present in semen of infertile men and fertile men with high sperm counts.
+*#*White blood cells in the semen may result from infection or inflammation in the proximal or distal male genital tract.
-**#'''<span style="color:#ff0000">Idiopathic</span>'''
+*#'''<span style="color:#ff0000">Spermatogenic problem where immature germ cells</span>''' (spermatocytes and/or round spermatids) '''<span style="color:#ff0000">are present in the ejaculate</span>'''
-**#*Most common cause
+*#*No evidence that elevated levels of immature sperm in the semen is deleterious to fertility, and they may be present in semen of infertile men and fertile men with high sperm counts.
-**'''Important to know whether men with elevated levels of round cells in the semen have immature germ cells or an infectious or inflammatory etiology for subsequent management (see below)'''
+*#'''<span style="color:#ff0000">Idiopathic</span>'''
-**'''Leukocytes and immature germ cells are not differentiable with light microscopy'''
+*#*Most common cause
-***'''Papanicolaou staining may be used'''
+*'''Important to know whether men with elevated levels of round cells in the semen have immature germ cells or an infectious or inflammatory etiology for subsequent management (see below)'''
-****Immunocytochemical staining provides more information to aid in distinguishing between inflammation and those subtypes involved in fighting off infection
+*'''Leukocytes and immature germ cells are not differentiable with light microscopy'''
-**'''<span style="color:#ff0000">Indications</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
+**'''Papanicolaou staining may be used'''
-***'''<span style="color:#ff0000">Increased round cells on semen analysis (>1million/mL)</span>'''
+***Immunocytochemical staining provides more information to aid in distinguishing between inflammation and those subtypes involved in fighting off infection
-****'''Upper limit of normal as <1 million white blood cells/mL of semen'''
+*'''<span style="color:#ff0000">Indications</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
-**'''<span style="color:#ff0000">Management</span>'''
+**'''<span style="color:#ff0000">Increased round cells on semen analysis (>1million/mL)</span>'''
-***'''<span style="color:#ff0000">If staining suggestive of</span>'''
+***'''Upper limit of normal as <1 million white blood cells/mL of semen'''
-****'''<span style="color:#ff0000">Pyospermia, evaluate for the presence of infection</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
+*'''<span style="color:#ff0000">Management</span>'''
-*****'''<span style="color:#ff0000">Sexual transmitted infections can also lead to leukocytes in semen and this needs to be ruled-out</span>'''
+**'''<span style="color:#ff0000">If staining suggestive of</span>'''
-*****'''Chronic prostatitis due to bacterial infection may require long courses of antibiotic treatment''', and some cases of elevated levels of white blood cells may result from chronic nonbacterial prostatitis.
+***'''<span style="color:#ff0000">Pyospermia, evaluate for the presence of infection</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
-*****Leukocytes can occur with UTIs, but unless urine is in the semen, this is an unlikely source.
+****'''<span style="color:#ff0000">Sexual transmitted infections can also lead to leukocytes in semen and this needs to be ruled-out</span>'''
-*****Inflammation may be medically treated with anti-inflammatory drugs.
+****'''Chronic prostatitis due to bacterial infection may require long courses of antibiotic treatment''', and some cases of elevated levels of white blood cells may result from chronic nonbacterial prostatitis.
-****'''<span style="color:#ff0000">Immature germ cells is a condition that cannot be treated</span>'''
+****Leukocytes can occur with UTIs, but unless urine is in the semen, this is an unlikely source.
-*'''Anti-sperm antibodies'''
+****Inflammation may be medically treated with anti-inflammatory drugs.
-** '''Can result in sperm agglutination in the semen'''
+***'''<span style="color:#ff0000">Immature germ cells is a condition that cannot be treated</span>'''
-***Anti-sperm antibodies may be present without sperm agglutination and, conversely, agglutination may be present due to other factors, such as the presence of E.coli in the semen
-** '''Can impair sperm-ova penetration'''
+===== Anti-sperm antibodies =====
-**'''Associated with events such as trauma, mumps orchitis, testis malignancy, vasal obstruction, vasectomy that disrupts the blood-testis barrier, or the patency of the male genital tract allowing sperm antigens or genital tract infections to generate anti-sperm antibodies.'''
+* '''Can result in sperm agglutination in the semen'''
-*** Vasectomy disrupts the blood-testis barrier, resulting in detectable levels of serum antisperm antibodies in 60% to 80% of men.
+**Anti-sperm antibodies may be present without sperm agglutination and, conversely, agglutination may be present due to other factors, such as the presence of E.coli in the semen
-** IgA and IgG antibodies are the predominant antibodies found in semen, while IgM is rarely found[https://pubmed.ncbi.nlm.nih.gov/33295257/]
+* '''Can impair sperm-ova penetration'''
-**Tests used (2):
+*'''Associated with events such as trauma, mumps orchitis, testis malignancy, vasal obstruction, vasectomy that disrupts the blood-testis barrier, or the patency of the male genital tract allowing sperm antigens or genital tract infections to generate anti-sperm antibodies.'''
-***Mixed antiglobulin reaction test
+** Vasectomy disrupts the blood-testis barrier, resulting in detectable levels of serum antisperm antibodies in 60% to 80% of men.
-***Immunobead (IB) test
+* IgA and IgG antibodies are the predominant antibodies found in semen, while IgM is rarely found[https://pubmed.ncbi.nlm.nih.gov/33295257/]
-****Gives information about the type and presence of the immunoglobulins and their localization specifically on the sperm head, midpiece or tail or covering the entire sperm
+*Tests used (2):
-**'''Indications'''
+**Mixed antiglobulin reaction test
-***'''Should not be done in the initial evaluation of male infertility'''
+**Immunobead (IB) test
-***'''Should only be considered if it will affect management of the patient.'''
+***Gives information about the type and presence of the immunoglobulins and their localization specifically on the sperm head, midpiece or tail or covering the entire sperm
-****'''For couples planning on ICSI, ASA testing should not be performed since it will not change management.'''
+*'''Indications'''
-**'''Management'''
+**'''Should not be done in the initial evaluation of male infertility'''
-***'''IUI after specific semen processing or ICSI'''
+**'''Should only be considered if it will affect management of the patient.'''
-****Some have reported improved IUI pregnancy rates with specific semen processing protocols for couples with anti-sperm antibodies compared to standard sperm washing, although the data are limited
+***'''For couples planning on ICSI, ASA testing should not be performed since it will not change management.'''
-****In those with anti-sperm antibodies, ICSI yields higher pregnancy rates per cycle than IUI with semen processing designed to disrupt the bound antibodies.
+*'''Management'''
-* '''Sperm aneuploidy testing'''
+**'''IUI after specific semen processing or ICSI'''
-**Involves the use of fluorescent molecular probes for chromosomes 13, 18, 21, X, Y because the presence of an extra chromosome for these specific chromosomes is consistent with a potentially viable but affected offspring. Aneuploidy of all other human chromosomes is not consistent with a viable offspring.[https://pubmed.ncbi.nlm.nih.gov/33295257/]
+***Some have reported improved IUI pregnancy rates with specific semen processing protocols for couples with anti-sperm antibodies compared to standard sperm washing, although the data are limited
-**'''Indications'''
+***In those with anti-sperm antibodies, ICSI yields higher pregnancy rates per cycle than IUI with semen processing designed to disrupt the bound antibodies.
-***'''Recurrent pregnancy loss'''
-*'''Sperm penetration assay''' most closely models incubational in vitro fertilization
+===== Sperm aneuploidy testing =====
-* '''Sperm culture: limited seminal concentrations of the majority of bacteria including E. Coli have minimal or no effects on sperm motility in vivo'''
+*Involves the use of fluorescent molecular probes for chromosomes 13, 18, 21, X, Y because the presence of an extra chromosome for these specific chromosomes is consistent with a potentially viable but affected offspring. Aneuploidy of all other human chromosomes is not consistent with a viable offspring.[https://pubmed.ncbi.nlm.nih.gov/33295257/]
+*'''Indications'''
+**'''Recurrent pregnancy loss'''
+===== 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'''
+===== Fructose =====
+*'''Produced in the male reproductive tract by the seminal vesicles and is released into the semen during ejaculation'''
+*Energy source for spermatozoa[https://pubmed.ncbi.nlm.nih.gov/11554980/ §]
+*Mean concentration of fructose in human semen is 2–3 mg/mL (11–16 μmol/mL)[https://pubmed.ncbi.nlm.nih.gov/11554980/ §]
+**'''Low semen fructose may suggest ejaculatory duct obstruction'''
 === Serum ===
-==== FSH and Total testosterone ====
+==== FSH and Morning Total Testosterone ====
 *'''<span style="color:#ff0000">Not recommended as a primary first-line test in the evaluation of male infertility[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]</span>'''
 *'''<span style="color:#ff0000">Indications (6):[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]</span>'''
@@ Line 353: / Line 390: @@
 ===== FSH =====
 * '''<span style="color:#ff0000">Indirect assessment of germ cell mass</span>'''
-** '''<span style="color:#ff0000">If reduced testicle size and FSH >7.6 IU/L --> consider spermatogenic dysfunction</span>'''
+** '''<span style="color:#ff0000">If testicle long axis < 4.6 cm and FSH >7.6 IU/L --> consider spermatogenic dysfunction</span>'''
-**'''If normal testicle size and FSH <7.6 IU/L --> consider obstructive azoospermia'''
+**'''<span style="color:#ff0000">If testicle long axis > 4.6 cm and FSH < 7.6 IU/L --> consider obstructive azoospermia'''
-===== Total testosterone =====
+===== Morning Total Testosterone =====
 *'''Should be defined based upon a morning blood sample,''' since levels drop during the day
 *'''≥300 ng/dL considered adequate (164 ng/dL bioavailable)'''
@@ Line 364: / Line 401: @@
 *#'''<span style="color:#ff0000">LH</span>'''
 *#'''<span style="color:#ff0000">Estradiol</span>'''
-*#'''<span style="color:#ff0000">Prolactin levels</span>'''
+*#'''<span style="color:#ff0000">Prolactin</span>'''
 *#*The relationship of testosterone, LH, FSH, and prolactin helps to identify the clinical condition.
@@ Line 403: / Line 440: @@
 === Post-ejaculate Urine Analysis ===
-* Used to diagnose retrograde ejaculation
+* '''Used to diagnose retrograde ejaculation'''
 * Viable sperm from urine or any location within the male reproductive tract can be used with ART to achieve a pregnancy.
@@ Line 417: / Line 454: @@
 * '''<span style="color:#ff0000">Karyotype and Y chromosome microdeletion</span>'''
-**'''<span style="color:#ff0000">Primary infertility and azoospermia or severe oligozoospermia (<5 million sperm/mL) with (3):</span>'''
+**'''<span style="color:#ff0000">Primary infertility and (3):</span>'''
-**# '''<span style="color:#ff0000">Elevated FSH OR</span>'''
+**#'''<span style="color:#ff0000">Azoospermia or severe oligozoospermia (<5 million sperm/mL) with elevated FSH OR</span>'''
-**# '''<span style="color:#ff0000">Testicular atrophy OR</span>'''
+**#'''<span style="color:#ff0000">Testicular atrophy OR</span>'''
-**# '''<span style="color:#ff0000">Presumed diagnosis of impaired sperm production as the cause of azoospermia</span>'''
+**#'''<span style="color:#ff0000">Presumed diagnosis of impaired sperm production as the cause of azoospermia</span>'''
 *'''<span style="color:#ff0000">Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation carrier testing (3):</span>'''
-*#'''<span style="color:#ff0000">Vasal agenesis/abnormalities</span>'''
+*#'''<span style="color:#ff0000">Vasal agenesis/abnormalities OR</span>'''
-*#'''<span style="color:#ff0000">Idiopathic obstructive azoospermia</span>'''
+*#'''<span style="color:#ff0000">Idiopathic obstructive azoospermia OR</span>'''
 *#'''<span style="color:#ff0000">If the female partner is a carrier (to consider for preimplantation diagnosis)</span>'''
@@ Line 450: / Line 487: @@
 === Renal ultrasound ===
 *'''Goal is to identify potential associated renal abnormalities.'''
-**The male genital tract is derived from the Wolffian or mesonephric tract. It is a paired organ, which forms the epididymis, vas deferens, and seminal vesicles during embryogenesis. As it connects to the primitive kidney, abnormalities in the Wolffian duct can lead to renal anomalies.
+**'''The male genital tract is derived from the Wolffian or mesonephric tract.''' It is a paired organ, which forms the epididymis, vas deferens, and seminal vesicles during embryogenesis. '''As it connects to the primitive kidney, abnormalities in the Wolffian duct can lead to renal anomalies.'''
-*'''<span style="color:#ff0000">Indications (2):</span>'''
+*'''<span style="color:#ff0000">Indications (1):</span>'''
 *#'''<span style="color:#ff0000">Congenital absence of the vas(a) (regardless of the CFTR status)</span>'''
-*#*≈26-75% of men with unilateral absence of the vas deferens will have ipsilateral renal anomalies including agenesis.
+*#*≈26-75% of males with unilateral absence of the vas deferens will have ipsilateral renal anomalies including agenesis.
-*#*≈10% of men with bilateral vasal agenesis will have ipsilateral renal anomalies including agenesis.
+*#*≈10% of males with bilateral vasal agenesis will have ipsilateral renal anomalies including agenesis.
-*#'''<span style="color:#ff0000">Patient with CFTR</span>'''
-*#*Even in men with CBAVD and CFTR mutations, unilateral renal agenesis may occur
 === Trans-rectal Ultrasound (TRUS) ===
-*Used to assess the anatomy of the primary organs/structures involved in ejaculation including the prostate, seminal vesicles, vasal ampulla, and ejaculatory ducts
+*Used to
+**Assess the anatomy of the primary organs/structures involved in ejaculation including the prostate, seminal vesicles, vasal ampulla, and ejaculatory ducts
+**Rule out ejaculatory duct obstruction
 *'''Should not be performed as part of the initial evaluation'''
 *'''<span style="color:#ff0000">Indications</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
 *#'''<span style="color:#ff0000">Semen analysis suggestive of ejaculatory dust obstruction (2):</span>'''
-*#*'''<span style="color:#ff0000">Low semen volume with</span>'''
+*#*'''<span style="color:#ff0000">Low semen volume with azoospermia and palpable vasa</span>'''
-*#**'''<span style="color:#ff0000">Azoospermia and palpable vasa</span>'''
+*#*'''<span style="color:#ff0000">Low semen volume and significant asthenospermia (total motility <40% or progressive motility <32%)</span>'''
-*#**'''<span style="color:#ff0000">Significant asthenospermia</span>'''
+*#**'''<span style="color:#ff0000">Normal semen is derived from testicular (~10%), prostatic (~20%), and seminal vesicle (~70%) fluid.'''
-*#***'''Normal semen is derived from testicular (~10%), prostatic (~20%), and seminal vesicle (~70%) fluid.'''
 *#***All components are androgen sensitive so that men with testosterone deficiency may have low semen volume and the utility of TRUS in such circumstances may be low.
-*#***'''Seminal vesicle fluid is alkaline. Obstruction that limits or prevents the seminal vesicle contribution will lead to acidic semen (pH <7.0)'''.
+*#***'''<span style="color:#ff0000">Seminal vesicle fluid is alkaline. Obstruction that limits or prevents the seminal vesicle contribution will lead to acidic semen (pH <7.0)'''.
 *#****Men with a normal semen pH are unlikely to have a complete distal genital tract obstruction.
 *#'''<span style="color:#ff0000">Symptoms (e.g., painful ejaculation)</span>'''
@@ Line 484: / Line 520: @@
 **'''<span style="color:#ff0000">Should not be routinely performed in the initial evaluation of the infertile male.</span>'''
 ***'''<span style="color:#ff0000">Routine use of ultrasonography to investigate presumed varicocele is to be discouraged</span>''', as treatment of non-palpable varicoceles is not associated with improved semen parameters and fertility rates as has been shown for treatment of clinical varicoceles.
-**'''<span style="color:#ff0000">May be used to if difficult to examine scrotum (obese patient or when the dartos muscle remains highly contracted during the physical exam)</span>'''
+**'''<span style="color:#ff0000">May be used if difficult to examine scrotum (obese patient or when the dartos muscle remains highly contracted during the physical exam)</span>'''
 === Abdominal imaging for isolated right varicocele ===
@@ Line 500: / Line 536: @@
 == Testicular biopsy ==
 * '''<span style="color:#ff0000">Should not routinely be performed to differentiate between obstructive azoospermia and non-obstructive azoospermia</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
-**Differentiation of obstructive azoospermia from non-obstructive azoospermia may most frequently be predicted from clinical and laboratory results without the need for surgical diagnostic biopsy.
+**'''Differentiation of obstructive azoospermia from non-obstructive azoospermia may most frequently be predicted from clinical and laboratory results without the need for surgical diagnostic biopsy.'''
-***FSH levels greater than 7.6 IU/L and testis longitudinal axis less than 4.6 cm indicate an 89% likelihood of spermatogenic dysfunction as the etiology
+***'''FSH > 7.6 IU/L and testis longitudinal axis < 4.6 cm indicate an 89% likelihood of spermatogenic dysfunction as the etiology'''
-***FSH levels less than 7.6 IU/L and testis longitudinal axes greater than 4.6 cm indicate 96% likelihood of obstruction as the etiology
+***'''FSH < 7.6 IU/L and testis longitudinal axes > 4.6 cm indicate 96% likelihood of obstruction as the etiology'''
-**In the infrequent cases with intermediate values, testis biopsy may be performed
+**'''In the infrequent cases with intermediate values, testis biopsy may be performed'''
+***'''Consider diagnostic and therapeutic biopsy if FSH and testicular volume normal but no clinical evidence of obstruction'''
+****May identify germ cell maturation arrest
 ***In the rare cases where testis biopsy is done primarily for diagnostic purposes, sperm cryopreservation from the sample should be attempted if ART is an option.
 * Spermatogenesis may be highly focal in men with azoospermia so a random biopsy may miss areas of sperm production
@@ Line 509: / Line 547: @@
 == Special Scenarios ==
 ===Recurrent pregnancy loss===
-*Defined as two or more failed pregnancies
+*'''Defined as ≥2 failed pregnancies'''
 **Distinct from infertility
 * Most miscarriages are related to abnormalities within the fetus itself[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]
@@ Line 518: / Line 556: @@
 *#'''Hematologic and immunologic disorders of the female partner'''
 *#'''Female partner endocrine issues (e.g., thyroid and diabetes)'''
-*#'''Male factor issues'''*#*'''Most common identified etiologic issues in males: karyotypic abnormalities and sperm DNA fragmentation.'''
+*#'''Male factor issues'''
+*#*'''Most common identified etiologic issues in males: karyotypic abnormalities and sperm DNA fragmentation.'''
 *'''Diagnosis and Evaluation (3):'''
 *#'''Karyotype'''
@@ Line 529: / Line 568: @@
 * '''Prior to commencement of gonadotoxic therapies and other cancer treatments, discuss the effects of therapy on sperm production with patients[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
-**Radiotherapy and chemotherapy used for cancer and other medical conditions can often lead to temporary or even long-term gonadal injury in men.
+**Radiotherapy and chemotherapy used for cancer and other medical conditions can lead to temporary or long-term gonadal injury.
 ***The recovery of sperm production following radiotherapy and/or chemotherapy depends on the survival of spermatogonial stem cells in the testis.
-****The recovery of sperm in the ejaculate may take months to years when the radiation dose exceeds 1 Gy; a dose exceeding 10 Gy will often result in permanent azoospermia
+****Radiation
-****Fractionated radiation (given over the course of weeks) may have a more detrimental effect on spermatogenesis than a single radiation dose
+*****The recovery of sperm in the ejaculate may take months to years when radiation dose > 1 Gy; dose > 10 Gy will often result in permanent azoospermia
-****Alkylating agents (e.g., procarbazine, cyclophosphamide, ifosfamide) and cisplatin target spermatogonial stem cells, and these drugs are the most likely to lead to permanent azoospermia at high doses
+*****Fractionated radiation (given over the course of weeks) may have a more detrimental effect on spermatogenesis than a single radiation dose
-****Most other chemotherapeutic agents (e.g., anthracyclines, microtubule inhibitors, antimetabolites, topoisomerase inhibitors) target differentiating germ cells in the testis (e.g., spermatids, spermatocytes, differentiating spermatogonia) and cause a transient reduction in sperm parameters with gradual recovery of sperm count observed three to six months after cessation of therapy.
+****Chemotherapy
-*****Topoisomerase II inhibitors (e.g., etoposide) are most toxic to spermatocytes with little to no toxicity to stem cells
+*****Alkylating agents (e.g., procarbazine, cyclophosphamide, ifosfamide) and cisplatin target spermatogonial stem cells, and these drugs are the most likely to lead to permanent azoospermia at high doses
-*****Doxorobucin targets differentiating spermatogonia and spermatocytes
+*****Most other chemotherapeutic agents (e.g., anthracyclines, microtubule inhibitors, antimetabolites, topoisomerase inhibitors) target differentiating germ cells in the testis (e.g., spermatids, spermatocytes, differentiating spermatogonia) and cause a transient reduction in sperm parameters with gradual recovery of sperm count observed three to six months after cessation of therapy.
-* Encourage men to bank sperm, preferably multiple specimens when possible, prior to commencement of gonadotoxic therapy or other cancer treatment that may affect fertility in men.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]
+******Topoisomerase II inhibitors (e.g., etoposide) are most toxic to spermatocytes with little to no toxicity to stem cells
+******Doxorobucin targets differentiating spermatogonia and spermatocytes
+* '''Encourage sperm banking, preferably multiple specimens when possible, prior to commencement of gonadotoxic therapy or other cancer treatment that may affect fertility[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
 **Couple may need to undergo several cycles of IVF treatment in order to achieve a pregnancy
-**Men presenting with cancer will generally have poorer semen parameters than normal donors, and their sperm respond less favorably to freeze-thawing (with poorer post-thaw motility) than donor sperm
+**Malespresenting with cancer will generally have poorer semen parameters than normal donors, and their sperm respond less favorably to freeze-thawing (with poorer post-thaw motility) than donor sperm
-*For azoospermic men with an intratesticular lesion, cryopreservation of testicular tissue should be considered during orchiectomy or excisional biopsy of the testicular lesion (an Onco-TESE approach)
+*'''For azoospermic men with an intratesticular lesion, cryopreservation of testicular tissue should be considered during orchiectomy or excisional biopsy of the testicular lesion (an Onco-TESE approach)'''
 *'''Inform patients undergoing a retroperitoneal lymph node dissection (RPLND) of the risk of aspermia and the availability of sperm banking prior to surgery.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
 **'''Obtain a post-orgasmic urinalysis for men with aspermia after RPLND who are interested in fertility.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
 ***Given the distribution of the nodes involved in drainage of the testes, the lumbar sympathetic nerve fibers responsible for ejaculation (T10-L2) are in close proximity to the node dissection templates.
 ***'''Sympathetic nerve fiber damage, such as that which can occur during a RPLND, can result in failure of the bladder neck to contract effectively allowing semen deposited into the prostatic urethra to pass in a retrograde fashion into the bladder (i.e., RE).[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]'''
-***As with any neural trauma, maximum recovery can take 12 to 24 months and thus, patients who have had nerve sparing RPLND should be told that return of antegrade ejaculation may take a protracted period of time. If aspermia remains 24 months after RPLND, then the patient should be informed that this is likely to be permanent.
+***'''As with any neural trauma, maximum recovery can take 12 to 24 months and thus, patients who have had nerve sparing RPLND should be told that return of antegrade ejaculation may take a protracted period of time.'''
+****If aspermia remains 24 months after RPLND, then the patient should be informed that this is likely to be permanent.
 * '''Inform patients undergoing chemotherapy and/or radiation therapy to avoid pregnancy for a period of at least 12 months after completion of treatment.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
-**One of the major concerns regarding the effects of gonadotoxic therapies in men wishing to father children is the induction of mutations in developing testicular germ cells. Studies have clearly demonstrated that radiation and chemotherapy can alter the genomic integrity of testicular germ cells.
+**One of the major concerns regarding the effects of gonadotoxic therapies in males wishing to father children is the induction of mutations in developing testicular germ cells.
-***The genomic damage induced by these treatments is germ cell stage specific.
+***Studies have clearly demonstrated that radiation and chemotherapy can alter the genomic integrity of testicular germ cells.
-**This implies that during and for a defined period of time after exposure to radiation and/or chemotherapy (depending on the susceptible germ cell) a man can produce an increased proportion of genetically abnormal spermatozoa. Conceiving a child during this period can substantially increase the risk of genetic mutations in the offspring.
+****The genomic damage induced by these treatments is germ cell stage specific.
+****This implies that during and for a defined period of time after exposure to radiation and/or chemotherapy (depending on the susceptible germ cell) a male can produce an increased proportion of genetically abnormal spermatozoa. Conceiving a child during this period can substantially increase the risk of genetic mutations in the offspring.
 *Consider informing patients that a SA performed after gonadotoxic therapies, should be done at least 12 months (and preferably 24 months) after treatment completion.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]
 **Studies demonstrate lowest sperm concentration by 12 months and maximization of recovery in the majority of studies between 2 to 3 years after the completion of treatment[https://pubmed.ncbi.nlm.nih.gov/33295257/]
@@ Line 565: / Line 608: @@
 # List 6 causes of low-volume semen.
 #What are the genetic tests in infertility? When are they indicated?
+== Mock Oral Exam ==
+* [https://www.youtube.com/watch?v=HXdKUcrJUac Azoozpermia] (Master the Medicine)
+*[https://www.youtube.com/watch?v=6gg9J-B-f8E Ejaculatory Duct Obstruction] (Master the Medicine)
+*[https://www.youtube.com/watch?v=USSSRzA2A80 Vasectomy] (Master the Medicine)
+*[https://www.youtube.com/watch?v=33Qopru4An8 Vasectomy Reversal and ART] (Master the Medicine)
+*[https://www.youtube.com/watch?v=EKZAXemK7-A Infertility] (Master the Medicine)
 == Next Chapter: [[Infertility: Management|Management of Infertility]] ==