CLINICAL OBSTETRICS AND GYNECOLOGY Volume 54, Number 4, 656665 r 2011, Lippincott Williams & Wilkins

Interpretation of the Semen Analysis and Initial Male Factor Management

PETER J. STAHL, MD,* DORON S. STEMBER, MDw and PETER N. SCHLEGEL, MD* *Weill Cornell Medical College and wMemorial Sloan Kettering Cancer Center, New York, New York

Abstract: A practical approach to semen analysis (SA) interpretation and the initial management of subfertile men is presented. Each parameter of the SA is described and management recommendations based upon SA findings are provided. The indications for and interpretation of adjunctive diagnostic testing for male factor subfertility are also discussed. Key words: semen analysis, subfertility, diagnostic testing

Introduction
Screening for male factor infertility with a reproductive history and at least 2 semen analyses (SA) is a critical component of evaluation for all subfertile couples, because a male factor causes or contributes to 40% to 60% of cases. Any abnormality
Correspondence: Peter N. Schlegel, MD, Starr 900, Department of Urology, New York Presbyterian/Weill Cornell, 525 East 68th Street New York, NY 10065 E-mail: pnschleg@med.cornell.edu P.S. is supported by grants from the Research Scholar program of the American Urological Association Foundation and the Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust. The authors declare that they have nothing to disclose.
CLINICAL OBSTETRICS AND GYNECOLOGY /

identified in the reproductive history or SA indicates the need for a full evaluation of the man. Male subfertility may be the presenting symptom of occult medical or genetically transmissible conditions that may threaten the health of patients or their offspring (Table 1). Moreover, identification of modifiable or treatable male factors may afford the health practitioner an opportunity to intervene and thereby optimize a couples fertility. A SA may help to recognize patients who should be evaluated for treatable male factors. Finally, untreatable conditions that are incompatible with biological paternity may be recognized, allowing avoidance of futile and costly attempts at assisted reproduction although, fortunately, these conditions are rare. Although the SA cannot be used in isolation to determine the etiology of male subfertility or the proper course of treatment, it is a highly informative and useful tool. Herein we present a practical approach to SA interpretation and initial male factor management.
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Interpreting the Semen Analysis

TABLE 1. Health-threatening Conditions That May Present With an Abnormal Semen Analysis

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Karyotypic abnormalities including Klinefelter syndrome Substance abuse including marijuana, alcohol, and anabolic steroids Kartagener syndrome (immotile cilia syndrome) Sexually transmitted infections Cystic fibrosis Systemic infections including viral illnesses and tuberculosis Hematologic malignancies Congenital or acquired hypogonadotropic hypogonadism Pituitary pathology including tumors, infiltrative diseases, and infarction Adrenal pathology including tumors and congenital adrenal hyperplasia Testicular pathology including germ cell cancers, interstitial cell tumors, infiltrative diseases, and primary testicular failure

TABLE 2. Reference Values for Semen Analysis Parameters Published by the World Health Organization in 1999 and 2010
Parameters
Semen volume pH Total sperm number Sperm concentration Total motility Progressive motility Sperm morphology

1999 WHO 2010 WHO Reference Value Reference Value

Z2.0 mL Z7.2 Z40 106 per ejaculate Z20 106 per mL NA* Z50% Z1.5 mL Z7.2 Z39 106 per ejaculate Z15 106 per mL Z40% Z32%

Z14% normal Z4% normal forms by forms by WHO criteria strict criteria

* The 1999 WHO manual excludes patients with grade c (nonprogressive) motility from discussion of reference values. NA indictes not applicable; WHO, World Health Organization.

Understanding SA
The SA is not a direct measure of fertility. There are no appropriate SA parameter cutoff numbers below which fertility is not possible because there is a considerable deal of overlap between fertile and infertile populations.1 Nonetheless, in 1999 and 2010 the World Health Organization (WHO) published lower reference limits for each semen parameter (Table 2).2 It is critical to recognize that these semen parameters do not reflect normal or average (mean) values, but a reflection of an attempt to identify minimum values, below which, men are at high risk of contributing to infertility in a couple. The 2010 lower reference limits are the statistical fifth percentile value for each SA parameter derived from an international population of fertile men who conceived within 12 months, and do not have a validated clinical relationship with subfertility. There may be a significant variation between semen parameters in different samples from a given patient. Therefore, at least 2 semen samples should be analyzed. A single normal sample may be

adequate to identify normal sperm production for fertility potential (assuming sexual function and sperm delivery is normal). It is preferable that the samples are collected over more than 1 spermatogenic cycle (2 mo), particularly if a recent insult to spermatogenesis such as viral illness or gonadotoxin exposure has occurred. Each sample should be collected after an ejaculatory abstinence period of 2 to 5 days. Samples should be collected in wide-mouthed, sterile containers, maintained as close as possible to body temperature, and analyzed within 1 hour. The semen sample is allowed to liquefy and is examined under wet mount light microscopy. The main parameters analyzed are ejaculate volume, pH, sperm concentration, total sperm number, sperm motility, and sperm morphology.
GROSS SEMEN CHARACTERISTICS

Freshly ejaculated semen is a gray-opalescent, semisolid coagulum that should spontaneously liquefy within 15 to 60 minutes. Substances in the seminal vesicle are www.clinicalobgyn.com

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Stahl et al resulting in low volume (<1.5 mL), fructose-negative, acidic ejaculate. Low semen volume in the setting of normal pH and positive fructose may suggest a degree of retrograde ejaculation or hypogonadism, but more commonly reflects incomplete collection. Management Low semen volume should be evaluated with hormonal testing and/or transrectal ultrasound. If testosterone (T) is low, then this may be the cause of impaired semen production by the prostate and/or seminal vesicles. High semen volume is not of pathologic significance unless excessive treatment is possible in those cases with IUI.
SPERM CONCENTRATION AND TOTAL SPERM NUMBER

responsible for coagulation, whereas liquefaction depends upon proteolytic enzymes derived from the prostate. Once liquefaction has occurred, semen viscosity is analyzed by allowing it to drop by gravity from a wide-bore pipette. Normal semen should fall in drops, whereas hyperviscous semen forms threads >2 cm long. Semen that is red or yellow may indicate hematospermia or jaundice. Abnormalities of liquefaction and viscosity may indicate the presence of infection, defects in prostatic proteolytic enzymes, or absence of the seminal vesicle or prostatic components. Management Men with viscous semen may have this condition managed with sperm washing and intrauterine inseminations (IUI). Other approaches have included systemic vitamin C or guanefesin, although the role of these agents is not well validated. Semen treatment with chymotrypsin or collagenase has also been reported.
SEMEN VOLUME AND pH

The normal semen volume is 1.5 to 5.0 mL and pH is 7.4 to 8.0. It is not clear if high semen volume reflects a pathologic condition. The seminal vesicles produce alkaline, fructose-positive fluid that comprises the majority (50% to 80%) of the ejaculate volume and is deposited in the urethra through the ejaculatory ducts and is thought to flush sperm from the prostatic urethra. Low semen volume typically reflects low seminal vesicle fluid volume, and more sperm may be trapped in the posterior urethra after ejaculation in this condition. Most of the remaining ejaculate is acidic (pH<7.0) fluid that is derived from the prostate and deposited directly in the urethra through prostatic ducts that do not communicate with the ejaculatory ducts. In men with ejaculatory duct obstruction, the seminal vesicle contribution to the ejaculate is lost, www.clinicalobgyn.com

Sperm numbers are reported as both concentration (millions of sperm/mL) and as total sperm count (concentration multiplied by semen volume in mL). Oligozoospermia refers to the state of having a sperm concentration below the traditional level of 20 million sperm/mL (WHO 2010: 15 million sperm/mL). Azoospermia refers to the complete absence of sperm in the ejaculate, which must be confirmed by absence of sperm in the pellet derived from centrifugation of the semen specimen. For this evaluation, the neat semen specimen should be centrifuged at Z1500g for at least 15 minutes before microscopic examination of the pellet. Azoospermia after centrifugation may reflect either complete obstruction of the male genital ductal systems or severe impairment of sperm production. Management The finding of impaired sperm concentration should lead to a full male history and physical examination and hormonal evaluation (for men with sperm concentration <10 million sperm/mL). This

Interpreting the Semen Analysis evaluation should be directed toward identification of correctable factors that may be affecting sperm production and/ or transport. For men with azoospermia, examination and hormone testing should lead to genetic testing based on the presumed diagnosis of obstruction or impaired production. For men with impaired production, karyotype and Y chromosome microdeletion analysis are indicated.
SPERM MOTILITY

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considered, if it will affect clinical management of the couple.

SPERM MORPHOLOGY

Sperm acquire motility as they pass through the epididymis. Motility is evaluated in 2 ways. Total motility refers to the percentage of sperm with flagellar movement, whereas progressive motility describes the percentage of sperm that demonstrate forward progression. The WHO previously suggested categorization of sperm into 4 categories: a for rapid progressive motility, b for slow or sluggish progressive motility, c for nonprogressive movement, and d for no movement. However, the 2010 WHO recommendation is to evaluate progressive motility with a simplified binary categorization in which sperm are classified as either forward progressive (rapid or sluggish) or nonprogressive. The state of having total motility <40% (previously 50%) or progressive motility below 32% is referred to as asthenozoospermia.

Management Impaired sperm motility can occur because of abnormal sperm production (see above comments re: low sperm production), varicocele, infection, antisperm antibodies, heat, or other toxic factors. In addition, men with persistently abnormal motility may be at higher risk of having abnormal sperm DNA fragmentation, so testing for this condition [with terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) or sperm chromatin structure assay (SCSA)] may be

Sperm morphology is recorded as the percentage of sperm that appear normally shaped on stained cytology smears. Traditional methods categorized sperm based on gross abnormalities of the head, midpiece, and tail (Fig. 1), whereas strict methodology categorizes sperm as normal only when strictly defined parameters of shape and appearance are met. Normal sperm morphology seems to have a role in fertility because only morphologically normal sperm will bind to the zona pellucida, thereby having a chance of fertilizing an oocyte. The percentage of sperm with normal morphology has been recognized as a factor that affects the chance of fertilization during in vitro fertilization (IVF). If intracytoplasmic sperm injection (ICSI) is applied, then even strict criteria morphology does not affect the chance of fertilization. The term teratozoospermia is used when the percentage of normal morphologic sperm is <4%. Because IVF involves selecting a relatively limited number of sperm for insemination with oocytes, it makes sense that percent normal morphology can affect the fertilization rate. However, it is not clear that % normal morphology affects the chance of pregnancy when men have normal numbers of sperm in the ejaculate, as 2% of 100 million provides more morphologically normal sperm than 4% of 15 million sperm (or the even lower numbers of sperm typically inseminated with an oocyte during IVF). Management The presence of abnormal morphology in an ejaculated semen specimen may not reflect any abnormality of fertility, especially if normal (60 to 80 million sperm/ mL) numbers of sperm are present in the ejaculate. If IVF is used for treatment, www.clinicalobgyn.com

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Stahl et al

FIGURE 1.

Commonly observed sperm morphologic abnormalities.

then abnormal morphology is generally considered an indication for ICSI. If abnormal sperm morphology is detected, it may reflect abnormal sperm production and full male evaluation can be considered. Abnormal morphology is not correlated with an increased risk of sperm aneuploidy or birth defects in offspring.
LEUKOCYTES AND IMMATURE GERM CELLS (ROUND CELLS)

document the presence of neutrophils/ leukocytes. Management The management of leukocytospermia is controversial, because antibiotic therapy has not been shown to decrease the presence of WBC in infertility patients with leukocytospermia. Most practitioners would evaluate persistent leukocytospermia with semen cultures and possibly antisperm antibody tests.

Approximately 20% of men have leukocytes in the seminal plasma. Clinically meaningful leukocytospermia is defined by the WHO as >1 million white blood cells (WBC)/mL. WBC are normally observed in prostatic fluid, but they may also be detected in pathologic states. Because leukocytes may be suggestive of infection or inflammation, it is important to differentiate them from immature germ cells, which are often observed in semen and are difficult to visually distinguish from leukocytes. Both appear as round cells and should be recorded as such unless specialized stains (such as peroxidase) or immunohistochemical techniques are used to www.clinicalobgyn.com

Extended Male Factor Evaluation

Although the complete SA is the cornerstone of the workup of the infertile man, it provides limited useful information when viewed in isolation from a patient. The history, physical examination, and select laboratory tests are all essential for further evaluation of an abnormal SA, and required for thoughtful formulation of an accurate diagnosis and directed treatment strategy. Complete evaluation and treatment of the infertile male will not

Interpreting the Semen Analysis be covered here, but the use of specialized tests that are indicated based on SA abnormalities will be overviewed.
EXTENDED ENDOCRINE EVALUATION

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INITIAL MALE ENDOCRINE EVALUATION

An intact hypothalamic-pituitary-gonadal axis is important for normal sperm production. The hypothalamus produces gonadotropin releasing hormone in a pulsatile fashion. Gonadotropin releasing hormone stimulates the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland. FSH acts on testicular sertoli cells to quantitatively and qualitatively maintain spermatogenesis. LH stimulates testicular Leydig cells to elaborate T, which is required in high concentrations within the testes for normal spermatogenesis. Serum T levels may not be the only appropriate marker of adequate intratesticular T concentrations, but they are a commonly used measure of normal hormones. 17-OH progesterone levels actually seem to more directly reflect intratesticular T levels and may be used to monitor intratesticular T for men who are on exogenous T treatment (that is generally contraindicated for men with interest in fertility). T is converted to estradiol (E) in the testes and in peripheral adipose tissue by the enzyme aromatase. Elaboration of LH and FSH is under negative feedback control mediated by T, E, and inhibin receptors in the hypothalamus and anterior pituitary. The best practice guidelines of the American Urological Association and American Society for Reconstructive Microsurgery recommend measuring T and FSH levels for men with sperm concentration <10 million/mL or with clinical findings suggestive of endocrinopathy.3 Some male reproductive specialists recommend checking serum T and FSH levels in all men with documented subfertility.

An extended hormonal evaluation is indicated if the history, physical examination, or initial endocrine evaluation (serum FSH and T) suggests an endocrinopathy. In men with low serum T, serum LH levels should be obtained to determine whether the disturbance is central or testicular, and is an important consideration when selecting hormonal therapy for appropriate patients. In men with low T (<150 ng/dL) associated with low FSH and LH (<1 IU/ L), magnetic resonance imaging of the sella turcica is indicated to evaluate for pituitary pathology. Serum prolactin should be measured in these patients, and in any man with decreased libido, sexual dysfunction, gynecomastia, or galactorrhea. Prolactinproducing microadenomas and macroadenomas may exert a negative effect on testicular function through suppression of gonadotropin release. The E level should be measured whenever gynecomastia or a testicular mass is present (to evaluate for a possible Leydig cell tumor), and may be useful in the selection of hormonal treatment when T levels are low.4

TESTING FOR GENITOURINARY INFECTION

Infections of the male reproductive tract may cause subfertility by obstructing the male genital ductal system, interfering with sperm production, exerting direct or indirect effects on sperm or sperm function, or by causing fertility disorders in female partners of infected men. Testing for infection is indicated if the initial history and physical examination suggest urethritis, prostatitis, epididymitis, or orchitis. However, there is neither consensus on which specimen should be tested (blood, urine, expressed prostatic secretions, or semen) nor the optimal assays for detection of infection. In asymptomatic men, the value of testing for genital tract infections is controversial, even when www.clinicalobgyn.com

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Stahl et al recommended.3 Chromosomal abnormalities account for 6% of all male infertility, with Klinefelter syndrome (47, XXY) being by far the most commonly identified anomaly. Y microdeletions are found in 10% of American men with severely impaired sperm production. Diagnosis is critical because 60% of the Y microdeletions identified in azoospermic men are incompatible with biological paternity, and in the remaining 40% the Y microdeletion and associated subfertile phenotype will be transmitted to male offspring.6 Genetic testing is also recommended in patients with unilateral or bilateral absence of the scrotal vas deferens. The diagnosis of vasal agenesis is made upon physical examination and will be missed if the male partner of a subfertile couple is not examined. Seventy percent of men with congenital bilateral absence of the vas deferens and no clinical symptoms of cystic fibrosis test positive for mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene,7 and most of those who test negative likely harbor less common mutations that are not included in the routine CFTR mutational screening panel. The female partners of all men with congenital bilateral absence of the vas deferens can also be tested, as the carrier rate for CFTR mutations is 4% among North American whites and negative testing of the male does not rule out abnormalities of the CFTR gene. The benefit of testing is in counseling affected patients about the risks of clinical cystic fibrosis and subfertility in their offspring, their siblings, and their siblings offspring.
ANTISPERM ANTIBODY TESTING

leukocytospermia (presence of >1 million WBC/mL) is present.5 Nonetheless, testing for aerobic and anerobic bacteria as well as Chlamydia trachomatis, Neisseria gonorrhea, and mycoplasma/ureaplasma are commonly advocated in leukocytospermic men or those with a history of infection.3 The goal of testing and antimicrobial therapy is to avoid transmission of infection to the female partner and to eliminate the adverse effects of infection on semen quality and sperm function.
ULTRASONOGRAPHY

Transrectal ultrasonography may be indicated in cases of azoospermia or severe oligozoospermia in which the history or SA results are suggestive of complete or partial ejaculatory duct obstruction (ejaculate volume <1.5 mL, pH<7.2).3 Ultrasonographic visualization of dilated seminal vesicles (>2 cm in anteroposterior diameter), dilated ejaculatory ducts, and/or midline prostatic cysts may support the diagnosis of ejaculatory duct obstruction, but definitive detection of obstruction requires documentation of sperm in the seminal vesicle in an azoospermic male with low semen volume.
GENETIC TESTING

Genetic causes of male subfertility warrant special consideration because they may be transmitted to offspring. These disorders predominantly affect severely oligozoospermic (<5 to 10 million sperm/mL) and azoospermic patients. Appropriately directed testing is indicated for all such men. Genetic counseling is mandatory before proceeding to treatment with assisted reproduction if an anomaly is detected. Patients with severe oligozoospermia or azoospermia, elevated serum FSH levels and small testes have impaired sperm production. In these men, karyotypic abnormalities and Y chromosome microdeletions are common and testing for each is www.clinicalobgyn.com

Antisperm antibodies (ASA) should be suspected in cases of isolated asthenozoospermia, when sperm agglutination (microscopic attachment of motile sperm to one another) is present, or when a high percentage of sperm with nonprogressive

Interpreting the Semen Analysis vibratory motility are identified on the postcoital test [this typically occurs because of female ASA].3 ASAs may inhibit sperm motility or transit through the female reproductive system, and may interfere with sperm survival, acrosome function, fertilization, and even embryo development. The most clinically useful tests examine semen for the presence of antibodies bound to sperm. Direct and indirect assays are available. The most common assay is the immunobead test during which sperm are mixed with beads that have been coated with secondary antibodies that bind to human immunoglobulin. Detection of ASA in semen may prompt medical treatment of the male partner and directs the utilization of assisted reproduction.
POSTEJACULATE URINALYSIS

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and dead sperm. The finding of high sperm viability in the presence of low or absent motility suggests impaired flagellar function that may result from sperm ultrastructural defects. Electron microscopy of ejaculated sperm can confirm a diagnosis of ultrastructural sperm microtubular defects and indicate the need for ICSI.
POSTCOITAL TEST

Evaluation of postejaculate urine for the presence of sperm is indicated in azoospermic or oligozoospermic men with low semen volume (<1.5 mL) in whom the vasa deferentia are palpable and the serum T level is normal.3 A urine sample is obtained immediately after ejaculation and centrifuged, after which the spun pellet is examined for sperm presence. Identification of any sperm in the postejaculate urine of an azoospermic man or many sperm in the postejaculate urine of an oligozoospermic man suggests the diagnosis of retrograde ejaculation.
SPERM VIABILITY TESTING

The postcoital test evaluates the interaction between the males sperm and his female partners cervical mucus. Although it is not required as a routine evaluation, it provides an important assessment of whether or not sperm are reaching and are able to penetrate the cervical mucus. Cervical mucus is obtained for microscopic examination just preceding ovulation but several hours after intercourse. The test is normal if >10 sperm are present per 400 field and 50% or more of the sperm are progressively motile. Postcoital testing is helpful in cases where it is not clear that the couple is having intercourse, or if hyperviscous semen, unexplained infertility, low or high ejaculate volume with normal sperm concentration, and/or abnormal penile anatomy is identified.
ANTIOXIDANT THERAPY

Isolated, severe consistent asthenozoospermia (<5% motility) should raise the suspicion for sperm ultrastructural defects. In these cases, the first step is sperm viability testing to determine whether the nonmotile sperm are alive or dead. Viability may be assessed with dye exclusion assays or with the hypoosmotic sperm swelling test, which both rely upon differences in membrane function between alive

There is a large body of in vitro and in vivo evidence that links reactive oxygen species in semen with sperm DNA damage and peroxidation of the sperm plasma membrane. However, clinical trials of antioxidant therapy for male subfertility have yielded conflicting results. There are no placebo-controlled trials that have demonstrated a significantly higher unassisted pregnancy rate when the male partner of a subfertile couple is treated with empiric antioxidant therapy. Nonetheless, several studies have demonstrated that antioxidant treatment may improve semen quality or sperm function. Furthermore, a recent Cochrane Collaboration www.clinicalobgyn.com

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Stahl et al to conceive. The chance of natural conception was 1.7% per cycle in patients with DFI>40%, compared with 15% per cycle for patients with DFI<8. Bungum et al10 examined DFI as a predictor of pregnancy with IUI and showed that the per cycle pregnancy and live delivery rates were 24% and 19% for patients with DFI<30, compared with 3% and 1.5% for patients with DFI>30. These 2 studies suggest that immediate IVF or ICSI may be indicated in men with high levels of sperm DNA damage in whom modifiable male factors are not present. In addition to the apparent relationship between abnormal sperm DNA integrity and failure to conceive with unassisted conception and IUI, abnormal sperm DNA integrity is associated with a lower pregnancy rate after application of IVF or ICSI in a large, wellperformed meta-analysis.11 In addition, high levels of sperm with abnormal DNA are associated with an approximately 2.5fold increased risk of pregnancy loss during assisted reproduction.12 Sperm DNA integrity testing may be helpful for evaluation of couples with recurrent pregnancy loss or multiple failed attempts at assisted reproduction. Antioxidants, repair of clinical varicoceles, and use of testicular sperm may be treatment options for couples with persistently abnormal sperm DNA integrity.
SPERM ANEUPLOIDY TESTING

meta-analysis8 showed statistically significant 4-fold to 5-fold increases in the pregnancy and live birth rates among subfertile men using assisted reproduction that are treated with antioxidants. Unfortunately, this meta-analysis could not identify which agents to recommend for treatment of infertile men, nor the appropriate dosage of any individual agent to use. Oral antioxidants for which at least1 welldesigned clinical trial has demonstrated a benefit include coenzyme Q, vitamins C and E, carnitine, glutathione, N-acetylcysteine, and selenium. The currently available evidence is insufficient to recommend one antioxidant over another. Choices of therapy should therefore be based upon physician experience and patient preference.
SPERM DNA INTEGRITY TESTING

Measurement of sperm DNA integrity has emerged as an additional measure of semen quality that may enable detection of occult male factors not identified on standard SA. The most commonly used, several available tests, are the SCSA and the TUNEL assay. The SCSA is a flow cytometric test that measures the stability of double-stranded sperm chromatin when exposed to a denaturant. Test results are given as the percentage of sperm with denatured (single-stranded) DNA, which is termed the DNA fragmentation index (DFI). In the TUNEL assay, individual sperm with DNA strand breaks are stained or labeled with a fluorophore. Results are given as the percentage of TUNEL-positive sperm. The clinical value of sperm DNA integrity testing is controversial. However, several studies suggest that it is useful in counseling subfertile couples about the likelihood of both unassisted and assisted conception. Spano et al9 showed that high DFIs on SCSA testing were inversely associated with the likelihood of unassisted conception among 215 couples with unknown fertility trying for the first time www.clinicalobgyn.com

Although not widely available, sperm aneuploidy testing may be indicated for men in couples with recurrent spontaneous miscarriage or multiple failed attempts at assisted reproduction. Although treatment options for abnormal sperm aneuploidy seem to be limited, such testing may help couples in considering other options for treatment, including use of donor sperm.

Conclusions
The SA functions as both a screening test for the presence of male factor infertility

Interpreting the Semen Analysis and as the cornerstone of the male factor evaluation. When the SA is abnormal, further evaluation of the male is indicated. SA results are used in concert with the patients history, physical examination, and serum hormone levels to direct specialized testing. In cases of recurrent failure of assisted reproduction or recurrent spontaneous miscarriage, additional sperm DNA, or genetic testing may be indicated.

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References
1. Guzick DS, Overstreet JW, FactorLitvak P, et al. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med. 2001;345: 13881393. 2. World Health OrganizationWHO Laboratory Manual for the Examination and Processing of Human Semen. 5th ed. Geneva: World Health Organization; 2010: 271. 3. Male Infertility Best Practice Policy Committee of the American Urological Association, Practice Committee of the American Society for Reproductive MedicineReport on optimal evaluation of the infertile male. Fertil Steril. 2006;86 (5 suppl 1):S202S209. 4. Sokol RZ. Endocrinology of male infertility: evaluation and treatment. Semin Reprod Med. 2009;27:149158.

5. Wolff H. The biologic significance of white blood cells in semen. Fertil Steril. 1995;63:11431157. 6. Stahl PJ, Masson P, Mielnik A, et al. A decade of experience emphasizes that testing for Y microdeletions is essential in American men with azoospermia and severe oligozoospermia. Fertil Steril. 2010; 94:17531756. 7. Chillon M, Casals T, Mercier B, et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med. 1995;332: 14751480. 8. Showell MG, Brown J, Yazdani A, et al. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2011;1: CD007411. 9. Spano M, Bonde JP, Hjollund HI, et al. Sperm chromatin damage impairs human fertility. The Danish First Pregnancy Planner Study Team. Fertil Steril. 2000; 73:4350. 10. Bungum M, Humaidan P, Axmon A, et al. Sperm DNA integrity assessment in prediction of assisted reproduction technology outcome. Hum Reprod. 2007; 22:174179. 11. Collins JA, Barnhart KT, Schlegel PN. Do sperm DNA integrity tests predict pregnancy with in vitro fertilization? Fertil Steril. 2008;89:823831. 12. Zini A, Boman JM, Belzile E, et al. Sperm DNA damage is associated with an increased risk of pregnancy loss after IVF and ICSI: systematic review and meta-analysis. Hum Reprod. 2008;23:26632668.

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