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    Optimal evaluation of_the_infertile_male Optimal evaluation of_the_infertile_male Document Transcript

    • ASRM PAGESDiagnostic evaluation of the infertilemale: a committee opinionThe Practice Committee of the American Society for Reproductive MedicineAmerican Society for Reproductive Medicine, Birmingham, AlabamaThe purpose of this ASRM Practice Committee report is to provide clinicians with principles and strategies for the evaluation of coupleswith male infertility problems. This revised document replaces, ‘‘Report on optimal evaluation ofthe infertile male,’’ most recently published in Fertil Steril 2006. (Fertil SterilÒ 2012;98:294–301. Use your smartphoneÓ2012 by American Society for Reproductive Medicine.) to scan this QR codeEarn online CME credit related to this document at www.asrm.org/elearn and connect to the discussion forum for this article now.*Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/goldsteinj-diagnostic-evaluation-infertile-male-a-committee-opinion/ * Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.A pproximately 8% to 15% of Ideally, the identification and and is warranted after 6 months for couples are unable to conceive treatment of correctable conditions couples in which the female partner is after one year of unprotected will improve the males fertility and over age 35 years (4). Men having con-intercourse (1). A male factor is solely allow conception to be achieved cerns about their future fertility alsoresponsible in approximately 20% of naturally. Detection of certain genetic merit evaluation.infertile couples and contributes in causes of male infertility provides the At a minimum, the initial screeninganother 30% to 40% of couples (2). A opportunity to inform affected couples evaluation of the male partner of anmale infertility factor is often defined about the risk for transmitting genetic infertile couple should include a repro-by abnormal semen parameters but abnormalities that may affect the ductive history and analysis of at leastmay be present even when the semen health of offspring, may affect the one semen sample. If the initial evalua-analysis is normal. The purpose of this chance for successful treatment, and tion is abnormal, then completedocument is to provide clinicians with which can help to guide treatment op- evaluation of the male partner isprinciples and strategies for the evalua- tions. Evaluation of the infertile male recommended.tion of couples with male infertility also is aimed at identifying any under-problems. lying medical conditions that may present as infertility. Some, such as tes- Reproductive HistoryGOALS OF EVALUATION ticular cancer and pituitary tumors, can The reproductive history should have serious health consequences if not include: 1) coital frequency and timing;Male infertility can be due to a variety properly diagnosed and treated (3). 2) duration of infertility and prior fertil-of conditions, many, but not all, of ity; 3) childhood illnesses and develop-which can be identified and treated. INDICATIONS FOR mental history; 4) systemic medicalWhen the cause of abnormal semen EVALUATION illnesses (such as diabetes mellitus andparameters cannot be identified, as is upper respiratory diseases); 5) previoustrue in many patients, the condition is Evaluation for infertility is indicated surgery; 6) medications and allergies;termed idiopathic. Rarely, patients for couples who fail to achieve a suc- 7) sexual history (including sexuallywith normal semen quality may have cessful pregnancy after 12 months or transmitted infections); and 8) expo-sperm that are either incapable of oo- more of regular unprotected inter- sures to gonadal toxins (includingcyte fertilization or harbor genetic course. Earlier evaluation and treat- environmental and chemical toxinsabnormalities that prevent normal fetal ment may be justified, based on and heat). A history of previous fertilitydevelopment. medical history and physical findings does not exclude the possibility ofReceived May 15, 2012; accepted May 22, 2012; published online June 13, 2012. a newly acquired, secondary, maleNo reprints will be available. infertility factor. Evaluation is theCorrespondence: Practice Committee, American Society for Reproductive Medicine, 1209 Montgom- ery Hwy., Birmingham, AL 35216 (E-mail: jgoldstein@asrm.org). same for men with primary infertility (never having fathered a pregnancy)Fertility and Sterility® Vol. 98, No. 2, August 2012 0015-0282/$36.00Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. and secondary infertility (having previ-doi:10.1016/j.fertnstert.2012.05.033 ously fathered a pregnancy).294 VOL. 98 NO. 2 / AUGUST 2012
    • Fertility and Sterility®Semen Analysis ICSI in those having isolated abnormalities in strictSemen analysis is the cornerstone of the laboratory evalua- morphology has been questioned (14).tion of the infertile male and helps to define the severity of Clinical reference ranges have been established for spermthe male factor. Physicians should provide patients with stan- concentration, motility, and morphology to help classify mendardized instructions for semen collection, including a defined as fertile or sub-fertile (15). The semen parameters of menpre-test abstinence interval of two to five days. Although with documented fertility have been compared to those ofa standard duration of abstinence is important for evaluation infertile men among couples participating in a clinical trialof semen parameters, some men with severe oligospermia can of superovulation and intrauterine insemination (IUI). Spermhave equal or better sperm concentration with a short (hours) parameters that predicted male fertility were a sperm concen-period of abstinence, supporting the potential use of multiple tration greater than 48 million/mL, sperm motility greatersemen analyses during assisted reproductive technology than 63%, and sperm morphology greater than 12% normal(ART) treatment cycles (5–7). Semen can be collected by (strict criteria). Parameters that predicted male subfertilitymasturbation into a specimen cup or by intercourse using were a sperm concentration less than 13.5 million sperm/special semen collection condoms that do not contain mL, sperm motility less than 32%, and sperm morphologysubstances toxic to sperm. Ideally, the specimen should be less than 9% normal. Values between the fertile and subfertilecollected at the laboratory. If collected at home, the thresholds were considered ‘‘indeterminate’’ (16). Althoughspecimen should be kept at room or body temperature each sperm parameter could predict fertility and subfertility,during transport and examined in the laboratory within one none was a powerful discriminator. It is important to empha-hour of collection. To ensure accurate results, the laboratory size that normal reference values for semen parameters do notshould have a quality control program for semen analysis reflect normal sperm concentration in the general population,that conforms to the standards outlined in the Clinical nor do they equate with the minimum values required for con-Laboratory Improvement Amendments (CLIA); additional ception; men with semen variables outside the referenceinformation including proficiency testing can be found on ranges may be fertile and, conversely, men having valuesthe CLIA website (8). within the reference range still may be infertile. The semen analysis provides information on semen vol-ume as well as sperm concentration, motility, and morphol- COMPONENTS OF A COMPLETE EVALUATIONogy (Table 1) (9). Methods for semen analysis are discussed FOR MALE INFERTILITYin many textbooks, and detailed laboratory protocols have When the initial screening evaluation reveals an abnormalbeen published by the World Health Organization (WHO) male reproductive history or demonstrates abnormal semen(10). The diagnosis of azoospermia can be established only parameters, a thorough evaluation by a urologist or otherafter the specimen is centrifuged (preferably at 3000 g) for specialist in male reproduction is indicated. More detailed15 minutes and the pellet is examined. The current WHO cri- evaluation of the male partner also should be considered interia for evaluating sperm morphology (10) are similar to the couples with unexplained infertility and those who remain‘‘strict criteria’’ described by Kruger (Tygerberg) (11, 12), in infertile after successful treatment of identified female infer-that relatively few sperm are classified as having normal tility factors.morphology, even in semen obtained from fertile men. The more thorough evaluation for male infertility shouldStrict sperm morphology has been used to identify couples expand on the screening evaluation by including a completeat risk for poor or failed fertilization using standard in vitro medical history and physical examination performed byfertilization (IVF) techniques (11) and thus to identify those a urologist or other specialist in male reproduction. Basedwho may be candidates for intracytoplasmic sperm on the results obtained, additional tests and procedures mayinjection (ICSI) (13). However, the value and necessity for be recommended including serial semen analyses, endocrine evaluation, post-ejaculatory urinalysis, ultrasonography, specialized tests on semen and sperm, and genetic screening. TABLE 1 Medical History Lower limits of the accepted reference values for semen analysis. The patients medical history can identify risk factors and On at least two occasions Reference value behaviors or lifestyles that could have significant impact on Ejaculate volume 1.5 mL male infertility. In addition to all of the elements of the repro- pH 7.2 ductive history described above, the medical history should be Sperm concentration 15 Â 106 spermatozoa/mL expanded to include 1) a complete review of systems; 2) fam- Total sperm number 39 Â 106 spermatozoa/ejaculate ily reproductive history; and 3) a detailed social history, in- Percent motility 40% Forward progression 32% cluding any past or current use of anabolic steroids, Normal morphology 4% normal recreational drugs, tobacco, and alcohol. And Sperm agglutination absent Viscosity %2 cm thread post-liquefaction Physical Examination Note: Data taken from World Health Organization, 2010 (10). A general physical examination is an integral part of the Practice Committee. Evaluation of the infertile male. Fertil Steril 2012. evaluation of infertile men. Particular attention should beVOL. 98 NO. 2 / AUGUST 2012 295
    • ASRM PAGESdirected to the genitalia including 1) examination of the pe- should be obtained in men who require a more thorough en-nis, noting the location of the urethral meatus; 2) palpation docrine evaluation.and measurement of the testes; 3) the presence and consis- Recently, the serum inhibin B concentration has emergedtency of both the vasa and epididymides; 4) the presence or as a marker for spermatogenesis. Inhibin B levels are signifi-absence of a varicocele; 5) secondary sex characteristics, in- cantly lower in infertile men than in fertile men and correlatecluding body habitus, hair distribution, and breast develop- better with sperm parameters than FSH levels (17). Given thement; and 6) digital rectal examination where indicated. significantly greater cost of measuring inhibin B, FSH cur-The diagnosis of congenital bilateral aplasia of the vasa def- rently remains the preferred test for screening purposes.erentia (CBAVD) is established by physical examination;scrotal exploration is unnecessary. Post-ejaculatory UrinalysisOTHER PROCEDURES AND TESTS FOR A low-volume or absent antegrade ejaculate suggests incom- plete semen collection, retrograde ejaculation, lack of emis-ASSESSING MALE INFERTILITY sion, ejaculatory duct obstruction, hypogonadism, orEndocrine Evaluation CBAVD. To exclude retrograde ejaculation, a post-Hormonal abnormalities of the hypothalamic-pituitary- ejaculatory urinalysis should be performed in men havingtesticular axis are well-recognized, but uncommon, causes an ejaculate volume less than 1.0 mL, except in those diag-of male infertility. Endocrine disorders are extremely uncom- nosed with hypogonadism or CBAVD. It also is important tomon in men with normal semen parameters. determine whether an improper or incomplete collection or An endocrine evaluation is indicated for men having: 1) a very short abstinence interval (less than 1 day) might beabnormal semen parameters, particularly when the sperm the cause.concentration is below 10 million/mL; 2) impaired sexual The post-ejaculatory urinalysis is performed by centri-function; or 3) other clinical findings that suggest a specific fuging the urine specimen for 10 minutes at 300 g, followedendocrinopathy. Some experts believe that all infertile males by microscopic examination of the pellet at 400Â magnifica-merit an endocrine evaluation, but there is no established tion. In men with azoospermia or aspermia, the presence ofconsensus of opinion. The minimum initial hormonal any sperm in the post-ejaculatory urinalysis suggests retro-evaluation should include measurement of serum follicle- grade ejaculation. In men with low ejaculate volume and oli-stimulating-hormone (FSH) and total testosterone concen- gospermia, ‘‘significant numbers’’ of sperm must be observedtrations. When the total testosterone level is low (<300 to support the diagnosis of retrograde ejaculation; there is nong/mL), a more extensive evaluation is indicated and should consensus of expert opinion on the minimum numberinclude a second measurement of total testosterone and required.measurements of serum free testosterone, luteinizing hor-mone (LH), and prolactin. Although serum gonadotropin Ultrasonographyconcentrations vary because they are secreted in a pulsatilemanner, a single measurement usually is sufficient to deter- Because nearly the entire male genital tract can be imagedmine the clinical endocrine status. The relationships among easily and accurately, ultrasonography is a useful tool forserum testosterone, LH, FSH, and prolactin concentrations detecting abnormalities of the male genital tract that mayhelp to provide an understanding of the source of abnormal adversely affect fertility. However, ultrasonography is onlytotal testosterone levels (Table 2). Whereas many men with indicated for a minority of infertile male patients.abnormal spermatogenesis have a normal serum FSH level, Transrectal ultrasonography. Normal seminal vesicles area markedly elevated serum FSH concentration clearly indi- usually less than 1.5 cm in antero posterior diameter (18).cates an abnormality in spermatogenesis. In individuals Transrectal ultrasonography (TRUS) revealing dilated semi-with an FSH level in the upper normal range, there may nal vesicles or ejaculatory ducts and/or midline cystic pros-be impaired spermatogenesis as well. Measurement of the tatic structures suggests, but does not by itself establish, thethyroid-stimulating hormone (TSH) concentration also diagnosis of complete or partial ejaculatory ductTABLE 2 Basal hormone levels in various clinical states. Clinical condition FSH LH Testosterone Prolactin Normal spermatogenesis Normal Normal Normal Normal Hypogonadotropic hypogonadism Low Low Low Normal Abnormal spermatogenesisa High/normal Normal Normal Normal Complete testicular failure/ High High Normal/low Normal hypergonadotropic hypogonadism Prolactin-secreting pituitary tumor Normal/low Normal/low Low High a Many men with abnormal spermatogenesis have a normal serum FSH, but a marked elevation of serum FSH is clearly indicative of an abnormality in spermatogenesis. Practice Committee. Evaluation of the infertile male. Fertil Steril 2012.296 VOL. 98 NO. 2 / AUGUST 2012
    • Fertility and Sterility®obstruction (19). Affected men typically produce a low- to large quantities of sperm antigens or after vasectomy. Riskvolume, acidic ejaculate containing no sperm or fructose. factors for ASA formation include trauma, torsion, biopsy,Men with CBAVD may exhibit similar findings because orchitis, testicular cancer, and vasectomy. Whereas indirectthey often have absent or atrophic seminal vesicles. Men antibody agglutination assays are used to detect ASA inwith partial ejaculatory duct obstruction often, but not al- serum or seminal plasma, a direct immunobead test is usedways, exhibit low semen volume, oligo-asthenospermia, to detect ASA (IgG and IgA) bound to the sperm head orand poor progressive motility. Some experts recommend tail. Sperm-bound antibodies are thought to be clinicallyroutine TRUS for oligospermic men having low volume important because they can decrease motility, block penetra-ejaculates, palpable vasa, and normal testicular size with tion of the cervical mucus and prevent fertilization andnormal serum testosterone. thereby decrease the likelihood for conception (22). AlthoughScrotal ultrasonography. Careful physical examination can some have suggested ASA testing for couples with unex-identify most scrotal pathology, including varicoceles, sper- plained infertility, the clinical utility of the test in such cou-matoceles, absent vasa, epididymal induration, and testicular ples is uncertain, and ASA testing is unnecessary if ICSI ismasses. Scrotal ultrasonography can identify occult varico- planned (23). One recent study has suggested that detectionceles that are not palpable, but such lesions have no demon- of serum ASA correlates with the presence of spermatogenesisstrated clinical significance (20). Scrotal ultrasonography can in men with azoospermia and can obviate the need for diag-be helpful for better defining vague or ambiguous physical nostic testicular biopsy to help determine whether obstructionexamination findings or abnormalities (including apparent is present. Men with azoospermia and ASA are likely to havemasses) and can be performed in men having testes located reproductive tract obstruction (24).in the upper scrotum, a small scrotal sac, or other anatomythat hinders physical examination. Testicular ultrasonogra- Sperm Viability Testsphy also should be considered for men presenting with infer-tility and risk factors for testicular cancer, such as Sperm viability can be assessed by mixing fresh semen withcryptorchidism or a previous testicular neoplasm. a supravital dye such as eosin Y or trypan blue, or by the use of the hypoosmotic swelling (HOS) test (10). These assays determine whether non-motile sperm are viable by identify-Specialized Clinical Tests on Semen and Sperm ing which sperm have intact cell membranes. In dye tests, vi-In some cases, semen analyses have failed to predict fertility able sperm actively exclude the dye and remain colorless,accurately, spurring a search for other methods that might while non-viable sperm readily take up the stain. Unfortu-improve the diagnostic evaluation of the infertile male. Gen- nately, sperm judged viable by dye tests cannot be used forerally, such specialized clinical tests should be reserved for IVF. In the HOS test, viable non-motile sperm, which swellcircumstances where results clearly will help to direct when incubated in a hypoosmotic solution, can be used suc-treatment. cessfully for intracytoplasmic sperm injection (25). Viable non-motile sperm can also be identified by incubation in pen-Quantitation of Leukocytes in Semen toxifylline. Viable sperm will develop motility after exposure to pentoxifylline (26).Increased numbers of white blood cells in semen have beenassociated with deficiencies in sperm function and motility.Under wet mount microscopy, leukocytes and immature Sperm DNA Fragmentation Testsgerm cells appear quite similar and are properly called ‘‘round DNA integrity is important for normal embryo development.cells.’’ Unfortunately, many laboratories improperly report all Sperm DNA integrity is maintained in part by the effect of di-round cells as ‘‘white blood cells’’ and, in men with such find- sulfide cross-links between protamines that allow for theings, the clinician must ensure that the two types of cells are compaction of chromatin in the nucleus. Sperm DNA damagedifferentiated. A number of methods are available to distin- can occur as a result of intrinsic factors, such as protamineguish leukocytes from immature germ cells, including tradi- deficiency and mutations affecting DNA compaction, ortional cytologic staining and immunohistochemical from extrinsic factors such as heat, radiation, and gonadotox-techniques (21). Men with true pyospermia (greater than 1 ins. The term ‘‘DNA fragmentation’’ refers to denatured ormillion leukocytes per mL) should be specifically evaluated damaged sperm DNA that cannot be repaired. A number ofto exclude genital tract infection or inflammation. clinical tests have been developed to measure sperm DNA fragmentation rates. Direct methods, such as the single-cellTests for Anti-sperm Antibodies gel electrophoresis assay (Comet) and terminal deoxynucleo-Anti-sperm antibodies (ASA) are a rare cause of male subfer- tidyl transferase dUTP nick end labeling (TUNEL) assays, spe-tility that do not require routine testing and are typically cifically analyze the number of breaks in the DNA. Indirecttreated with ICSI. Testing for ASA has historically been tests like the Sperm Chromatin Structure Assay (SCSA) definedone when the semen analysis reveals isolated asthenosper- abnormal chromatin structure as an increased susceptibilitymia (with normal sperm concentration) or sperm agglutina- of sperm DNA to acid-induced denaturation in situ (27).tion. ASAs can be found in the serum, seminal plasma, or Threshold values used to define an abnormal test are greaterbound directly to sperm. ASAs can form when there is a breach than or equal to 25% to 27% for the SCSA (28) and greaterin the blood-testis barrier and the immune system is exposed than or equal to 36% for TUNEL assays (29).VOL. 98 NO. 2 / AUGUST 2012 297
    • ASRM PAGES Sperm DNA damage is more common in infertile men and membrane conductance regulator (CFTR) gene. When indi-may contribute to poor reproductive performance in some cated, efforts to identify genetic causes for infertility cancouples. Sperm DNA damage is also associated with sponta- have a major impact on the choice and outcome of treatment.neous recurrent miscarriage. However, existing data relating Cystic fibrosis gene mutations. There is a strong associationto the relationship between abnormal DNA integrity and between CBAVD and mutations of the CFTR gene, which isreproductive outcomes are too limited to routinely recom- located on chromosome 7 (37). Almost all men with clinicalmend any of these tests for males in an infertile couple, but cystic fibrosis exhibit CBAVD. Additionally, as many asthe effect of abnormal sperm DNA fragmentation on the value 80% of men with CBAVD have documented mutations ofof IUI or IVF and ICSI results may be clinically informative the CFTR gene. Failure to detect a CFTR abnormality in men(30). Although no treatment for abnormal DNA integrity with CBAVD does not exclude the presence of a mutationhas proven of clinical value, varicocele repair and antioxidant that cannot be identified with currently available methods.use may affect sperm DNA integrity. Sperm retrieved from the Therefore, men with CBAVD should be assumed to havetestis tend to have better sperm DNA quality in men with a CFTR gene mutation. To determine the risk of conceivingabnormal ejaculated sperm DNA integrity. Because the prog- a child affected with CF, it is important to test the female part-nostic clinical value of DNA integrity testing may not affect ner of an affected man. Even if the female partner is negativetreatment of couples, the routine use of DNA integrity tests by currently available testing, the couple remains at some riskin the clinical evaluation of male factor infertility is contro- because some of the less common mutations may be missedversial (31). unless the entire gene is sequenced. The prevalence of CFTR mutations also is increasedLess Commonly Used Specialized Tests among men with azoospermia related to congenital bilateralNumerous other tests of sperm function have been employed obstruction of the epididymides and those with unilateralpredominantly in research studies. Sperm penetration assays vasa agenesis. Consequently, genetic evaluation should bemay detect defects in sperm-fertilizing capacity and could considered for those having either abnormality. Some menidentify patients who will benefit from application of ICSI. presenting with either unilateral or bilateral vasal agenesisHowever, since ICSI is routinely used during IVF for male- and unilateral renal agenesis have the mesonephric duct ab-factor infertility couples, this test is rarely of any clinical normalities associated with hereditary renal adysplasiavalue. The acrosome reaction of human sperm can be detected (HRA) which has an autosomal dominant form of inheritanceusing specialized staining techniques. Rates of spontaneous with incomplete penetrance and variable expression. Theseacrosome reactions and acrosome reactions induced by patients do not have CFTR mutations and require geneticagents such as calcium ionophore and progesterone have counseling prior to IVF (38, 39).been measured. Sperm from infertile men tend to demonstrate Karyotypic chromosomal abnormalities. The prevalence ofhigher acrosome levels spontaneously, but lower levels in the chromosomal abnormalities is increased in infertile menpresence of inducers (32). A number of biochemical tests of and inversely proportional to sperm count; the prevalence issperm function have been studied, including measurements 10%–15% in azoospermic men (40), approximately 5% inof sperm creatine kinase (33) and reactive oxygen species men with severe oligospermia (<5 million/mL), and less(ROS). ROS appear to be generated by both seminal leukocytes than 1% in men with normal sperm concentrations (41).and sperm cells and can interfere with sperm function by per- Sex chromosomal aneuploidy (Klinefelter syndrome;oxidation of sperm lipid membranes and creation of toxic 47,XXY) accounts for about two-thirds of all chromosomalfatty acid peroxides (34). Other tests and procedures have abnormalities observed in infertile men (42). The prevalencebeen used to select sperm for ICSI and may identify gametes of structural autosomal abnormalities, such as inversionswith better quality, including hyaluronic acid binding, mem- and balanced translocations, also is higher in infertile menbrane maturity testing, apoptotic evaluation, and magnified than in the general population (43). Couples wherein thesperm examination (35). However, these tests have a very lim- male has a gross karyotypic abnormality are at increasedited role in the evaluation of male infertility because they risk for miscarriages and for having children with chromo-have limited clinical utility and typically do not affect somal and congenital defects. Therefore, men with non-treatment. obstructive azoospermia or severe oligospermia should be evaluated with a high-resolution karyotype before using theirGenetic Screening sperm to perform ICSI.Genetic abnormalities can cause infertility by affecting sperm Y-chromosome microdeletions. Microdeletions of clinicallyproduction or sperm transport. Men with non-obstructive relevant regions of the Y chromosome have been found inazoospermia and severe oligospermia (<5 million/mL) are at 7% of infertile men with severely impaired spermatogenesisincreased risk for having a genetic abnormality compared to compared with 2% of normal men. However, the percentagefertile men (36). The most common genetic abnormalities of men with Y-chromosome microdeletions increases tofound in such men are numerical and structural chromosomal 16% in men with azoospermia or severe oligospermia (44).aberrations that impair testicular function, and Y-chromo- Such microdeletions are too small to be detected by standardsome microdeletions that are associated with isolated defects karyotyping, but can be identified using polymerase chain re-in spermatogenesis. In addition, men with CBAVD can be action techniques to analyze sequence tagged sites that haveassumed to have an abnormality of the cystic fibrosis trans- been mapped along the entire length of the Y chromosome.298 VOL. 98 NO. 2 / AUGUST 2012
    • Fertility and Sterility®Most deletions causing azoospermia or oligospermia occur in a meaningful risk assessment to couples based on the testregions of the long arm of the Y chromosome (Yq11) known results (55).as the Azoospermia Factor (AZF) regions, designated asAZFa (proximal), AZFb (central), and AZFc (distal). It appearsthat these regions, and possibly other regions of the Y chro- SUMMARYmosome, contain multiple genes necessary for spermatogen-  An initial screening evaluation of the male partner of anesis. For example, the DAZ (deleted in azoospermia) gene, infertile couple is indicated when pregnancy has notwhich encodes a transcription factor usually present in men occurred after 12 months of unprotected intercourse orwith normal fertility, is located in the AZFc region. after 6 months of failure to conceive when the female is The specific location of the deletion along the Y chromo- greater than 35 years. Earlier evaluation may be warrantedsome influences its impact on spermatogenesis. Many men when medical history and physical findings indicate orwith a microdeletion in the AZFc region of the Y chromosome suggest specific male or female infertility risk factors andhave severe oligospermia. Others with AZFc region deletions for men who question their reproductive potential.are azoospermic but still may produce sufficient numbers of  A thorough evaluation by a urologist or other specialist insperm to allow testicular sperm extraction. Sperm production male reproduction, including a complete medical andin such men appears to be stable over time, and the results of reproductive history and physical examination, should beICSI are not affected adversely by the AZFc deletion (45). In performed if the initial screening evaluation reveals ancontrast, deletions involving the entire AZFb region appear abnormal male reproductive history or demonstratesto predict a very poor prognosis for sperm retrieval (46). The abnormal semen parameters. Additional tests aimed atsame may be true for men having deletions involving the defining the cause may be required.entire AZFa region of the Y chromosome (47). Sons of individuals with Y-chromosome microdeletionswill inherit the abnormality and, therefore, also may be infer- CONCLUSIONStile (48). Although a microdeletion of the Y chromosome is notknown to be associated with other health problems, few data  The initial evaluation for male factor infertility shouldexist regarding the phenotypes of the sons of fathers with include a reproductive history and at least one properlysuch genetic abnormalities. A recent report showed that performed semen analysis, if normal.some men with Y-chromosome microdeletions had abnor-  Endocrine evaluation is indicated for men having: 1)malities of the pseudoautosomal regions (PARs) of the Y chro- abnormal semen parameters, particularly when the spermmosome. Although most of these men had some sperm concentration is below 10 million/mL; 2) impaired libidoproduction, 16% of men had genetic aberrations of the or sexual function; or 3) other clinical findings that suggestshort-stature-homeo-box (SHOX) gene, the best known a specific endocrinopathy. At a minimum, initial evalua-gene in PAR1. SHOX gene abnormalities are associated with tion should include measurement of the serum testosteroneshort stature, mental retardation and arm and wrist defor- and FSH concentrations.mities (49). It is important to note that a negative Y-chromo-  A post-ejaculatory urinalysis is indicated for men havingsome microdeletion test result does not necessarily exclude an ejaculate volume less than 1.0 mL, except in those diag-a genetic abnormality, because there may be other, currently nosed with hypogonadism or CBAVD.unknown, gene sequences on the Y or other chromosomes  Trans-rectal ultrasonography (TRUS) for diagnosis of ejac-that also might be required for normal spermatogenesis. Con- ulatory duct obstruction is indicated for men with azoo-versely, some Y-chromosome microdeletions are rarely found spermia, palpable vasa, and low ejaculate volumes. TRUSin fertile or subfertile males who have fathered children (44, also is indicated for men with oligospermia, low volume50). Y-chromosome analysis should be offered to men who ejaculates, palpable vasa, and normal testicular size.have non-obstructive azoospermia or severe oligospermia  Scrotal ultrasonography is indicated for men whose phys-before performing ICSI with their sperm. ical examination is difficult or inadequate and when a tes- ticular mass is suspected.  Less commonly used specialized tests on semen (spermSPERM CHROMOSOME ANEUPLOIDY DNA fragmentation testing, acrosome reaction, ROS) areSperm DNA aneuploidy can be assessed by fluorescent in situ useful investigative tools but are not recommended forhybridization (FISH) technology (51). One study has reported the routine evaluation of infertile men. Such tests may bethat up to 6% of men presenting with infertility and a normal considered in the evaluation of unexplained infertilitykaryotype had an increased frequency of meiotic alterations but generally have little clinical utility.detectable in their sperm (52). Men with the highest risk of  Genetic testing for CFTR mutations (to rule out the possibil-sperm aneuploidy are those with karyotypic abnormalities, ity of offspring affected with cystic fibrosis) should beseverely abnormal sperm morphology, and non-obstructive offered to the female partner of men with CBAVD beforeazoospermia (51). Patients with recurrent pregnancy loss proceeding with treatments that use sperm from theand recurrent IVF failure may also benefit from sperm aneu- affected man.ploidy testing (53, 54). Currently, limitations to the routine  Men with non-obstructive azoospermia or severe oligo-use of this technology include cost, inability to screen the spermia (<5 million/mL) are at increased risk for havingactual sperm used in ICSI, and difficulty in assigning a definable genetic abnormality and should be offeredVOL. 98 NO. 2 / AUGUST 2012 299
    • ASRM PAGES karyotype and Y-chromosome analysis before performing 10. World Health Organization. WHO laboratory manual for the examination ICSI using their sperm. Genetic counseling may be offered and processing of human semen, 2010. Available at: http://www.who.int /reproductivehealth/publications/infertility/9789241547789/en/index.html. when a genetic abnormality is suspected in either the male Last accessed May 24, 2012. or female partner and should be provided whenever a ge- 11. Kruger TF, Acosta AA, Simmons KF, Swanson RJ, Matta JF, Oehninger S. netic abnormality is detected. Predictive value of abnormal sperm morphology in in vitro fertilization. Fertil Steril 1988;49:112–7.Acknowledgments: This report was developed under the 12. Menkveld R, Stander FS, Kotze TJ, Kruger TF, van Zyl JA. The evaluation of morphological characteristics of human spermatozoa according to stricterdirection of the Practice Committee of the American Society criteria. Hum Reprod 1990;5:586–92.for Reproductive Medicine as a service to its members and 13. Pisarska MD, Casson PR, Cisneros PL, Lamb DJ, Lipshultz LI, Buster JE, et al.other practicing clinicians. Although this document reflects Fertilization after standard in vitro fertilization versus intracytoplasmicappropriate management of a problem encountered in the sperm injection in subfertile males using sibling oocytes. Fertil Steril 1999;practice of reproductive medicine, it is not intended to be 71:627–32.the only approved standard of practice or to dictate an exclu- 14. Keegan BR, Barton S, Sanchez X, Berkeley AS, Krey LC, Grifo J. Isolatedsive course of treatment. Other plans of management may be teratozoospermia does not affect in vitro fertilization outcome and is not an indication for intracytoplasmic sperm injection. Fertil Steril 2007;88:appropriate, taking into account the needs of the individual 1583–8.patient, available resources, and institutional or clinical prac- 15. Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM,tice limitations. The Practice Committee and the Board of et al. World Health Organization reference values for human semen charac-Directors of the American Society for Reproductive Medicine teristics. Hum Reprod Update 2010;16:231–45.have approved this report. 16. Guzick DS, Overstreet JW, Factor-Litvak P, Brazil CK, Nakajima ST, The following members of the ASRM Practice Committee Coutifaris C, et al. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 2001;345:1388–93.participated in the development of this document. All Com- 17. Kumanov P, Nandipati K, Tomova A, Agarwal A. Inhibin B is a better markermittee members disclosed commercial and financial relation- of spermatogenesis than other hormones in the evaluation of male factorships with manufacturers or distributors of goods or services infertility. Fertil Steril 2006;86:332–8.used to treat patients. 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