This article summarizes the current office-based evaluation of male infertility and offers speculation, based on current research, on the future evolution of this encounter. A comprehensive history, physical examination, and semen analysis remain paramount to directing the evaluation; however, new advances continue to refine diagnostic and treatment algorithms. Interpretation of the routine semen analysis as well as adjunctive assessments, including reactive oxygen species, DNA fragmentation, and fluorescent in situ hybridization (FISH) are discussed. The analysis of genetic and endocrine abnormalities is reviewed.
Key points
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A comprehensive history and physical examination remains an essential component of the infertility evaluation.
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No single semen analysis parameter is a powerful discriminator of fertility and semen analysis reference ranges are not the minimum values required for conception.
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Endocrine testing is recommended in men with oligospermia, azoospermia, or history and physical examination findings suggestive of hormonal abnormalities.
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A karyotype and Y-chromosome microdeletion assay are indicated in men with a sperm concentration less than or equal to 5 million/mL, nonobstructive azoospermia, or clinical suggestions of an abnormality.
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DNA fragmentation and fluorescent in situ hybridization testing are replacing some of the previously used evaluations of sperm function (eg, postcoital test, sperm penetration assay).
Introduction
There is nothing more important to life than reproduction. Infertility is not only a challenging and stressful condition for patients and physicians but is also major public health concern that results in rippling psychosocial effects. It is estimated that approximately 7.3 million couples seek infertility care annually in the United States. Infertility is due a male factor alone in approximately 30% of these couples, while combined male and female factors comprise an additional 20%. In a study from the US Center for Disease Control, 7.5% of all sexually experienced men reported seeing a physician for a fertility evaluation, and 18.1% of men evaluated were found to have male-factor infertility. Although the use of assisted reproductive technology (ART) has steadily increased and currently contributes to 1.4% of all births in the United States, the number of male reproductive procedures performed is on the decline. Men from infertile couples often do not seek evaluation. Additionally, couples in which the man has significant semen abnormalities are often immediately directed toward in vitro fertilization (IVF) or other forms of ART, effectively bypassing the male evaluation completely. This trend is quite concerning given numerous recent studies closely linking male fertility with overall male health, cardiovascular fitness, and the development of cancer. Moreover, treatable causes of infertility or other medical problems are often discovered during the male evaluation.
There have been dramatic advances in the diagnosis and treatment of male infertility during the past several decades. Since 1992 with the introduction of intracytoplasmic sperm injection (ICSI), which allows for conception with only a single sperm, there has been rapid growth in the understanding of the genetic basis for male infertility. Examples include the elucidation of the relationship between cystic fibrosis mutations and congenital bilateral absence of the vas deferens (CBAVD), as well as the identification of Y-chromosome microdeletions. Similarly, microsurgical techniques for sperm retrieval and reconstruction have resulted in continued success. Considering the latest advances in the evaluation of the subfertile man, the goal of this article is to describe the essential components of the history, physical examination, and laboratory and radiographic studies in the initial office evaluation, and offer our vision of the future in male-infertility evaluation.
Introduction
There is nothing more important to life than reproduction. Infertility is not only a challenging and stressful condition for patients and physicians but is also major public health concern that results in rippling psychosocial effects. It is estimated that approximately 7.3 million couples seek infertility care annually in the United States. Infertility is due a male factor alone in approximately 30% of these couples, while combined male and female factors comprise an additional 20%. In a study from the US Center for Disease Control, 7.5% of all sexually experienced men reported seeing a physician for a fertility evaluation, and 18.1% of men evaluated were found to have male-factor infertility. Although the use of assisted reproductive technology (ART) has steadily increased and currently contributes to 1.4% of all births in the United States, the number of male reproductive procedures performed is on the decline. Men from infertile couples often do not seek evaluation. Additionally, couples in which the man has significant semen abnormalities are often immediately directed toward in vitro fertilization (IVF) or other forms of ART, effectively bypassing the male evaluation completely. This trend is quite concerning given numerous recent studies closely linking male fertility with overall male health, cardiovascular fitness, and the development of cancer. Moreover, treatable causes of infertility or other medical problems are often discovered during the male evaluation.
There have been dramatic advances in the diagnosis and treatment of male infertility during the past several decades. Since 1992 with the introduction of intracytoplasmic sperm injection (ICSI), which allows for conception with only a single sperm, there has been rapid growth in the understanding of the genetic basis for male infertility. Examples include the elucidation of the relationship between cystic fibrosis mutations and congenital bilateral absence of the vas deferens (CBAVD), as well as the identification of Y-chromosome microdeletions. Similarly, microsurgical techniques for sperm retrieval and reconstruction have resulted in continued success. Considering the latest advances in the evaluation of the subfertile man, the goal of this article is to describe the essential components of the history, physical examination, and laboratory and radiographic studies in the initial office evaluation, and offer our vision of the future in male-infertility evaluation.
The history and physical examination
History
Couples with normal fertility may be counseled that pregnancy rates by intercourse are approximately 20% to 25% per month, 75% by 6 months, and 90% by 1 year. Ten percent of fertile couples take longer than 1 year to conceive naturally. The accepted definition of infertility by the American Society for Reproductive Medicine is the inability to conceive naturally within 12 months. Despite this definition, a basic fertility workup should be initiated for any couple desiring one, with concurrent assessment of each partner. It is becoming more common that couples delay parenthood until after career development, or they may have questions or anxiety about their fertility status before attempts to conceive. For these reasons, a simple, cost-effective evaluation should be available for attempts at natural conception. This allows for earlier diagnosis and treatment of potential problems as well as alleviation of anxiety, which itself may be therapeutic.
A thorough, careful, and methodical history is necessary for successful diagnosis and treatment of male infertility because of the broad potential causes, including genetic, congenital, medical, surgical, environmental, and even psychosocial sources. The key components of the history and physical examination in the male-infertility workup are summarized in Table 1 . The most efficient interview is with the couple. Because spermatogenesis lasts, on average, 64 days, careful attention to the patient’s history over the previous 2 to 3 months, especially recent fevers, other illnesses, substance abuse, and gonadotoxin exposures. Evaluation should be repeated in 3 months, if necessary. The history should begin with discussion of the duration of the couple’s infertility, previous fertility treatments, previous pregnancies, and a detailed reproductive and sexual history, followed by a thorough past general medical and surgical history, social history, family history, and review of systems.
| Reproductive History | Medication and Drug Use |
| Past and current attempts at pregnancy | Testosterone, anabolic steroids |
| Methods of birth control | Recreational drugs (eg, marijuana, narcotics) |
| Sexual technique | Alcohol and tobacco |
| Timing of intercourse (ovulatory prediction) | Antibiotics |
| Use of lubricants | Immunosuppressants |
| Menstrual history | |
| Prior female evaluation | |
| Sexual History | Occupational and Lifestyle Exposures |
| Erectile dysfunction | Chronic heat (eg, laptops) |
| Hypogonadal symptoms | Benzene-based solvents |
| Sexually transmitted infections | Pesticides and herbicides |
| Ejaculatory dysfunction | Heavy metals |
| Childhood Conditions | Review of Systems |
| Cryptorchidism | Respiratory and sinus infections |
| Hypospadias | Anosmia |
| Congenital anomalies | Galactorrhea |
| Age at puberty | Visual field deficits |
| Systemic Illnesses | Physical Examination (general) |
| Fevers or recent illness | Body habitus (eg, obesity, Klinefelter) |
| Diabetes | Gynecomastia |
| Spinal cord injury | Secondary sexual characteristics |
| Infectious or inflammatory (eg, epididymitis) | |
| Cancer Treatment | Physical Examination (genitalia) |
| Chemotherapy | Penis: hypospadias, chordee, venereal lesions |
| Radiation | Testis: size, consistency, contours, masses |
| Epididymis: induration, cysts or spermatoceles | |
| Surgical History | Vas deferens: agenesis, atresia, granuloma |
| Hernia repair or other inguinal surgery | Spermatic cord: asymmetry, varicocele |
| Scrotal trauma | Rectal examination: cyst, dilated seminal vesicles |
| Testicular torsion | Inguinal examination: surgical scars |
| Retroperitoneal, pelvic, prostatic or bladder | |
| Orchiopexy | |
| TURP | |
| Family History | |
| Infertility | |
| Genetic disorders (eg, cystic fibrosis) | |
| Consanguinity |
The reproductive and sexual history may begin with a survey of the couple’s sexual behavior. Infertility attributable to sexual behavior may be present in up to 5% of couples. One of the most commonly reported misconceptions is the frequency and timing of intercourse around ovulation. The authors recommend that intercourse should be performed every other day beginning 5 days before expected ovulation until 5 days after. An inquiry into the use of lubricants, which may be spermatotoxic or impair motility, is also advised.
The history should additionally elicit information on past medical and surgical history stemming all the way to childhood. Report of genitourinary anomalies, reconstructive surgery, or pediatric illness associated with prolonged fevers or hospitalization may prove relevant. A history of pubertal mumps orchitis can result in subfertility in 13% of men. In utero or childhood exposure to chemotherapy, radiation, or hormones may result in defects in spermatogenesis.
Cryptorchidism can have negative implications for fertility even with appropriate timing of surgical correction. Despite treatment, 13% and 34% of men with unilateral and bilateral cryptorchidism, respectively, will demonstrate azoospermia. If left untreated, these rates are much higher. Surgery for testicular torsion or pediatric hernia repair can similarly affect future paternity. Childhood hernia repairs have been associated with a 26.7% incidence of vasal obstruction.
Clinicians should also inquire into common diseases of adulthood, including diabetes mellitus, sleep apnea, infectious diseases (eg, HIV, gonorrhea, chlamydia), neurologic disorders, and trauma. These illnesses may have implications for fertility and affect emission, ejaculation, or potentially result in obstruction of the male reproductive system.
Pharmacologic or environmental exposures should similarly be addressed. Environmental toxins may include synthetic estrogens associated with pesticide use, organic solvents in paints or inks, ionizing radiation in nuclear power plant plants, and heavy metals in manufacturing. These agents may result in disruption of hormonal regulation or have direct toxic effects on spermatogenesis. Prescription and recreational drugs can also impair sperm production and function. Tobacco and nicotine exposure can impair sperm concentration, motility, and morphology, and increase DNA fragmentation rates. Caffeine, alcohol, and marijuana similarly have gonadotoxic effects, whereas narcotics are known to affect gonadotropin secretion, which results in lower serum testosterone. Exposure to exogenous anabolic steroids can cause suppression of serum gonadotropins and intratesticular testosterone. This effect ultimately will result in impaired spermatogenesis. Cessation of steroid use can result in a reversal of spermatogenic arrest; however, recovery can take up to 2 years, if it occurs at all.
Recovery of spermatogenesis can similarly be unpredictable in patients exposed to the effects of chemotherapy and radiation. In patients with a history of malignancy, clinicians should inquire about the chemotherapeutic agents used, duration of treatment, dose, number of cycles, and sperm banking. Likewise, patients treated with radiation should be queried about dose, duration, and any efforts toward gonadal shielding. In men presenting with infertility, testis cancer and Hodgkin lymphoma are the two most common malignancies encountered. Both have excellent survival rates; however, each is associated with impairment of spermatogenesis. Chemotherapeutic agents and radiation will pose additional detriment to this baseline impairment.
In addition, patients with testicular cancer may have required a retroperitoneal lymph node dissection, which can result in sympathetic chain injury and retrograde ejaculation or anejaculation. This necessitates inquiry into past surgical history, which is warranted in all patients presenting for infertility. Similar to childhood hernia repairs, vasal occlusion rates in adult patients undergoing surgery with mesh approach 20%.
Solicitation of history from the female partner is additionally required. It should include age, history of pelvic surgery or infections, known uterine or tubal abnormalities, exposure to gonadotoxins, and a history of endometriosis or ovulatory irregularity. Additional relevant history should include pregnancies and complications, infertility with another partner, cycle length and characteristics, coital frequency, sexual dysfunction, pelvic infections or surgery, use of prescription or recreational drugs, pelvic pain, thyroid dysfunction, dyspareunia, and hirsutism.
Physical Examination
As with the initial history, the physical examination can reveal information critical to the infertility evaluation. External appearance, such as body habitus, can be an indicator of underlying endocrine or genetic abnormalities. In addition, impaired maturation, gynecoid distribution of pubic hair, and gynecomastia may reveal androgen deficiency. Similarly, location of the urethral meatus should be assessed as hypospadias can result in improper placement of semen within the vaginal vault and, when accompanied with other congenital defects, may represent an underlying chromosomal abnormality.
Examination of the inguinal and scrotal regions should include assessment for scars, testis size and consistency, varicocele, and presence of the vas deferens and epididymides. Average testicular size, which should be measured via orchidometer or calipers, is 4.6 cm in length, 2.6 cm in width, and 18 to 20 cm 3 in volume. Diminishment of testicular size may be an indication of impaired spermatogenesis or androgen deficiency. Palpation of both vasa can help rule out CBAVD, and consistency of the epididymes can be assessed for the presence of induration, epididymal cyst, or spermatocele, which may indicate obstruction.
Examination of the spermatic cord should include palpation for varicocele with the patient in a standing position performing a Valsalva maneuver. Varicoceles represent the most common anatomic abnormality identified in infertile men. Digital rectal examination allows for the evaluation of the prostate, midline cysts, and the presence of enlarged seminal vesicles. Transrectal ultrasound (TRUS) is required in men with a significant finding on digital rectal examination.
Initial laboratory assessment
The Semen Analysis
The cornerstone of the initial laboratory assessment of the infertile man is the semen analysis. Given the inherent intraindividual variability in semen analysis results, a minimum of two analyses is recommended. Patients should be given specific instructions regarding collection, including an ideal abstinence period of 2 to 3 days. A shorter abstinence period may affect concentration, whereas a prolonged abstinence may affect motility. Collection should be done via masturbation or with special seminal collection condoms lacking spermicidal agents. Transportation of the specimen should be at body temperature with arrival at the laboratory within 1 hour of collection.
The semen is analyzed regarding its physical characteristics, such as pH and viscosity, as well as the volume, sperm concentration, motility, and forward progression, strict morphology, and the presence of round cells. Other investigative parameters may vary by laboratory. The most commonly used reference ranges are those of the World Health Organization (WHO) with the most recent iteration from 2010 ( Table 2 ). There are many additional specialized tests of sperm form and function; however, the traditional semen analysis remains the core of the evaluation. The remaining tests help to narrow the differential diagnosis and direct treatment.
| Parameter | Lower Reference Limit |
|---|---|
| Volume (mL) | 1.5 |
| pH | ≥7.2 |
| Sperm concentration (10 6 per mL) | 15 |
| Total sperm number (10 6 per mL) | 39 |
| Total motility | 40 |
| Progressive motility | 32 |
| Strict morphology (normal forms, %) | 4 |
The Endocrine Evaluation
Endocrine causes of male infertility are present in less than 3% of cases. An endocrine evaluation is indicated in men with oligospermia, azoospermia, or history or physical examination findings suggestive of hormonal abnormalities. Information obtained from the history may include complaints of sexual dysfunction, delayed puberty, or diminished libido, and the physical examination may reveal findings of decreased androgenization such as gynecomastia. In contrast, men with a normal semen analysis do not routinely require assessment of gonadotropins. Most endocrinopathies are found in men with sperm concentrations of less than 10 million sperm per mL. The initial hormone assessment should include a serum follicle-stimulating hormone (FSH) and testosterone. Morning determinations of testosterone are preferred given its well-described diurnal variation. A more comprehensive evaluation includes luteinizing hormone (LH), prolactin, estradiol, free testosterone, and sex hormone binding globulin, which should be obtained when abnormalities are present on the initial evaluation. With assessment of testosterone, FSH, and LH, differentiation between hypergonadotropic hypogonadism (primary testicular failure), hypogonadotropic hypogonadism, androgen resistance, and hyperprolactinemia is possible. Of note, men with profound hypogonadism (testosterone <150 ng/dL) or hyperprolactinemia require a pituitary MRI to evaluate for pituitary adenoma. For further discussion of the endocrine evaluation, see an article by Hotaling and colleagues, elsewhere in this issue.
Imaging in the male infertility office evaluation
Ultrasound is the most common imaging modality used in the evaluation of male infertility. Scrotal color Doppler ultrasound may be used to confirm a suspicious diagnosis of a varicocele. Although a clinically significant varicocele is typically diagnosed and graded by physical examination alone, the ancillary use of ultrasound may be required in patients in whom the physical examination is limited. This may include cases of obesity, tight or small scrotums, previous surgery, altered anatomy, or inability to tolerate the examination. Reversal of blood flow with a Valsalva maneuver and the presence of spermatic veins greater than 3 mm are accepted ultrasound criteria for the diagnosis of varicocele. Ultrasonography may also identify additional pathologic conditions affecting fertility, including testicular tumors, spermatoceles, seminal vesicle atresia, ejaculatory cysts, and renal disorders associated with CBAVD.
In men with CBAVD, TRUS may reveal absence of the ampullae of the vas deferens or seminal vesicle abnormalities. TRUS is also frequently used in patients with low-volume azoospermia, severe unexplained oligoasthenospermia, palpable abnormalities on digital rectal examination, and when ejaculatory duct obstruction (EDO) is suspected. EDO can be the result of infection or inflammation leading to stenosis, compression from median cysts, or atonic or enlarged seminal vesicles such as those in patients with diabetes and adult polycystic kidney disease, respectively. Visualization of seminal vesicles greater than 1.5 cm in anteroposterior diameter is considered suggestive of EDO, and seminal vesicle aspiration may be performed concurrently to confirm the diagnosis.
Other imaging modalities, including MRI, are used selectively in the evaluation of male infertility. MRI may prove valuable in patients with renal, seminal vesicle, vasal, urethral, or other pelvic abnormalities not fully visualized with ultrasound. MRI is more commonly used in the workup of profound hypogonadism (testosterone <150 ng/dL) and hyperprolactinemia to rule out pituitary adenoma.
Interpretation of the initial evaluation
Following completion of a thorough history, physical examination, initial semen analysis, and an endocrine evaluation, if required, a diagnostic differential can typically be established. Further testing allows for refinement of the diagnosis and delineation of treatment options. Much of the infertility evaluation can be organized into a systematic approach that lends itself to diagnostic and treatment algorithms. Semen analysis results can be characterized by defects in individual parameters, including seminal volume, concentration, motility, and morphology, or those involving multiple abnormalities. Despite the formation of clinical reference ranges for semen analysis findings, no single parameter is a powerful discriminator of fertility. Normal reference ranges are not equivalent to the minimum values required for conception nor do they reflect the normal reference values for sperm concentration in the general population. Men with values outside the normal ranges may be fertile and those within reference ranges may be infertile.
Normal Semen Parameters
Of men presenting for an initial infertility evaluation, 30% will demonstrate normal semen parameters. One may consider further testing in these men because some will show functional defects, which can impair fertilization. Additional assessments may include reactive oxygen species (ROS) or DNA fragmentation. Further tests, which are less commonly used in the modern era of ART, include antisperm antibodies (ASAs), the postcoital test, sperm penetration assay, hemizona assay, and acrosome reaction testing that may be used in very select cases. These assays have fallen out of favor because ICSI is routinely used during IVF for couples with male-factor infertility; therefore, the potential clinical benefit has diminished. For further detail on functional assays, see an article by Centola, elsewhere in this issue. The shifting paradigms in testing for male infertility are further delineated in Table 3 .
| Traditional Methods | Modern Methods |
|---|---|
| Routine semen analysis | Strict morphology |
| Light microscopy | DNA fragmentation |
| ASAs | Fluorescent in situ hybridization testing |
| Postcoital test | Y-chromosome microdeletion assay |
| Sperm penetration assay | ROS |
| Hemizona assay | Genomic microarrays |
| Sperm acrosome reaction | — |
If functional defects are identified, the possibility for treatable causes must be reexamined. If deficiencies are identified that are not treatable, these couples should be counseled regarding IVF with ICSI. In those men without functional sperm defects, a contributing female factor should be ruled out and intrauterine insemination (IUI) or IVF may be considered. All men presenting with normal semen parameters should be counseled regarding coital timing and lifestyle changes, such as discouragement of certain lubricants, hot tubs, hot baths, and saunas.
Defects in isolated semen parameters
Seminal Volume Abnormalities
The lower limit of adequacy for semen volume, based on WHO standards, is 1.5 mL (see Table 2 ). Complete absence of the ejaculate (aspermia) occurs when no antegrade fluid is produced during male orgasm. The absence of semen may be due to retrograde ejaculation in which semen travels through the open bladder neck into the bladder. Failure of emission occurs when no semen transits through the vas deferens and ejaculatory ducts into the posterior urethra. Ejaculation may be impaired by neurologic disorders, such as spinal cord injury and diabetes; the use of α-blockers for benign prostatic hypertrophy; or retroperitoneal and colonic surgery that resulted in injury to the sympathetic nerves. Ejaculatory failure should be differentiated from azoospermia, in which no sperm are present in the ejaculate, and from anorgasmia, in which orgasm is not reached based on patient report.
Low-volume ejaculates are usually due to incomplete collection. Other contributing factors may be short abstinence periods, lack of emission, EDO, hypogonadism, CBAVD, or partial retrograde ejaculation. In patients at risk for retrograde ejaculation and those with ejaculate volumes of less than 1.0 mL, a postejaculate urinalysis should be performed. The finding of greater numbers of sperm in the urine than the ejaculate indicates a significant component of retrograde ejaculation; however, there is no consensus on the minimum number of sperm required to be diagnostic of retrograde ejaculation. Any sperm in the postejaculatory urinalysis is also useful in ruling out complete EDO.
It follows that, in absence of sperm in the postejaculatory urine, EDO should be suspected. The typical semen analysis pattern of complete EDO is azoospermic, acidic, low volume, and fructose-negative. TRUS can rule out EDO through visualization of seminal vesicles less than 1.5 cm in anteroposterior diameter. Dilated seminal vesicles found at the time of TRUS should be aspirated for sperm. The presence of millions of sperm under microscopic examination of the seminal aspirate is diagnostic of EDO. The diagnosis of partial EDO may be considered in the setting of low volume, oligoasthenospermia with normal testis size, and hormones. In these patients, the antegrade sample typically provides enough sperm for ART, although transurethral dilation of the stenotic ejaculatory ducts can be considered.
Abnormalities in Sperm Concentration
Oligospermia
Attempts to survey populations of men in hopes of defining normal or mean sperm density have yielded inconsistent results. Similarly, studies showing longitudinal changes and diminishment of semen quality in large populations have only added confusion as to what constitutes a normal semen analysis. The WHO defines oligospermia as a density of less than 15 million/mL sperm (see Table 2 ). Eight percent of men presenting with infertility will demonstrate oligospermia. In men with less than 10 million sperm per mL, testing of serum FSH and testosterone is advised because this will detect most clinically significant endocrinopathies. Varicocele is another common finding in men with oligospermia; however, it is more commonly associated with combined abnormalities of sperm concentration, motility, and morphology.
Men with severe oligospermia, defined as less than 5 million/mL, are at increased risk of genetic abnormalities. A karyotype and Y-chromosome microdeletion analysis should be performed in these patients. For patients with an isolated abnormality in concentration, therapy should be directed toward correcting hormonal deficiencies and identification of genetic abnormalities. For those in whom a cause is not determined, ART may be used.
Azoospermia
Four percent of men presenting for an infertility evaluation will demonstrate azoospermia. The diagnosis of azoospermia can only be established after the specimen is centrifuged at 3000 g for 15 minutes and the pellet examined. Following the diagnosis of azoospermia, delineation of nonobstructive azoospermia (NOA) versus obstructive azoospermia (OA) is necessary. NOA is defined by a deficiency of spermatogenesis, whereas OA represents adequate sperm production in the setting of ductal obstruction. The physical examination can be used to help differentiate between these two entities. Testicular size and the presence of vasa should be noted. As with severe oligospermia, these men require testing for an endocrinopathy as well as a karyotype and Y-chromosome microdeletion analysis. Men with NOA generally exhibit atrophic testes and an elevated FSH, indicating failure of spermatogenesis, whereas the finding of normal testis size and a normal FSH raises the possibility of OA. Obstructive causes may include CBAVD, vasectomy, EDO, and vasal or epididymal obstruction secondary to injury or infection (see later discussion). Men found to have CBAVD require testing for cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations (see later discussion).
In select cases, a testicular biopsy, performed as an in-office testicular sperm aspiration (TESA), can help differentiate between defects in spermatogenesis and obstruction. In patients with NOA, the role of testicular biopsy is most often limited to microsurgical testicular sperm extraction (micro-TESE) in conjunction with IVF and ICSI. Testicular biopsy as a diagnostic tool to differentiate NOA from OA was recently questioned in men with an FSH greater than or equal to 7.6 mIU/mL and a testicular long axis less than or equal to 4.6 cm because these men are statistically most likely to have NOA. The problem with this approach lies in the inherent variability in FSH between laboratories, making these absolute criteria less useful.
The presence of normal numbers of sperm on biopsy confirms OA. Location of the obstruction may be further delineated intraoperatively via scrotal exploration and vasal fluid aspiration in conjunction with vasal irrigation or contrast vasography. For further discussion of the surgical management of azoospermia, see an article by Schlegel and colleagues, elsewhere in this issue. In summary, in the azoospermic patient, the endocrine and genetic evaluation is imperative in directing management. Office TESA may be useful in select cases. If genetic abnormalities are found, referral for genetic counseling should be offered before proceeding with ART.
Abnormalities in motility
Sperm motility is routinely defined by the percentage of motile sperm and the quality of the movement of forward progression. WHO criteria delineate the normal percentage of motile sperm to be 40%, with 32% demonstrating progressive motility (see Table 2 ). Low sperm motility is observed in 25% of all abnormal semen analyses. Isolated asthenospermia typically denotes a low percentage of sperm demonstrating any movement or sperm that have poor forward progression. Potential causes include prolonged abstinence, partial EDO, genital tract infections, pyospermia, ASAs, ultrastructural sperm defects, or varicoceles. Asthenospermia associated with agglutination suggests the presence of ASAs, which may be directly assayed, or leukocytospermia (ie, excessive white blood cells in the ejaculate). Patients without treatable causes of severe asthenospermia are usually directed to ART. Hormonal testing in the setting of isolated asthenospermia is not indicated.
Nonmotile sperm are typically nonviable; however, in cases of uncertainty, viability staining may be used. Necrospermia is the finding when all sperm are nonviable. In some cases, men with absent or low (5%–10%) motility and normal-to-high viability will have ultrastructural defects. These sperm should be examined with electron microscopy. The most common disorder associated with these ultrastructural abnormalities is primary ciliary dyskinesia, also known as immotile cilia syndrome.
Abnormalities in morphology
Defects in morphology, also termed teratospermia, may be due to the presence of varicoceles, but more commonly are idiopathic. Rare ultrastructural defects, including globozoospermia (absence of the acrosome), may also be found. Guzick and colleagues have previously demonstrated that the percentage of sperm with normal morphology had greater power to discriminate between fertile and infertile men than concentration and motility. In contrast, Nallella and colleagues reported that motility and concentration provide more accurate information compared with morphology. Almost half of the fertile men in the Nallella series, however, presented with abnormal morphology, making this criteria a less useful discriminator.
Strict morphology was developed in hopes of enhancing the prognostic value of morphologically normal spermatozoa. These criteria were originally established in 1986 by Kruger and colleagues and now include a smooth oval head measuring 3 to 5 mm in length and 2 to 3 mm in width; a well-defined acrosome, comprising 40% to 70% of the head; an absence of defects of the neck, midpiece or tail; and an absence of cytoplasmic droplets larger than half the size of the head.
In 2010, the WHO established Kruger strict morphology as the new standard reference for sperm morphology in comparison to the more commonly and historically used light microscopy. This new threshold established 4% as the lower reference limit of strictly normal forms. The predictive value of strict morphology in successful reproductive techniques has been inconsistent. In 1994, Grow and colleagues, demonstrated IVF fertilization rates of 94% when sperm morphology was normal (>14%), 88% with 4% to 14% normal forms, and 15% when fewer than 4% of forms were normal. This led the investigators to conclude that strict morphology was an excellent biomarker of sperm fertilizing capacity, independent of motility and concentration. Later studies found similar results regarding the predictive value of strict morphology in IVF with and without ICSI and IUI. Other investigators have not confirmed these findings. For example, Keegan and colleagues found that isolated teratospermia did not affect IVF outcome and concluded that it is not an indication for ICSI.
A high percentage of sperm in the ejaculate must be abnormal before strict criteria can begin to predict poor fertilization in these couples, indicating that abnormal morphology does not always equate with abnormal function. Strict morphology remains a useful component of the fertility evaluation, although isolated abnormalities in strict morphology should not immediately prompt use of IVF. Natural conception and IUI remain possible for these couples.
Multiple semen abnormalities
Oligoasthenoteratozoospermia (OAT) reflects semen analysis abnormalities in sperm density, motility, and morphology. Thirty-seven percent of men presenting for infertility will have defects in two or more semen parameters. The most common cause of OAT on semen analysis is the presence of a varicocele. A varicocele is a clinical diagnosis, established by physical examination and without the use of ultrasonography. Subclinical or occult varicoceles found only on scrotal ultrasonography are not considered clinically `significant and do not warrant correction. Additional causes of OAT may include fever, gonadotoxin exposure, certain medications, cryptorchidism, and partial EDO.
Varicocele is the most common correctable cause of male infertility and its therapeutic effect extends to all aspects of patients exhibiting OAT, with potential improvements in concentration, motility, and morphology. Further study may extend the benefits of varicocele repair to improvements in hypogonadism. Varicocelectomy remains relevant in the modern era because it has been shown to improve IVF outcomes and reduce the complexity of ART. For further discussion of varicoceles, see an article by Brannigan and colleagues, elsewhere in this issue.
Other seminal abnormalities
Leukocytospermia
Leukocytospermia, large numbers of white blood cells in the semen, has been associated with abnormalities in sperm motility and function. Using traditional light microscopy, distinguishing between round cells, which can represent leukocytes or immature germ cells, can be difficult. The use of immunohistochemical staining or monoclonal antibodies is required to make this determination. Pyospermia is defined as greater than 1 million leukocytes per mL and it requires evaluation for genital tract infection or inflammation. Cytokines and ROS released by inflammatory cells can impair sperm motility and viability. Men with elevated leukocytes should have a semen culture performed, although this test is infrequently positive for significant noncommensal organisms. Empiric antibiotic therapy is not warranted because it generally does not provide significant benefit and many commonly prescribed antibiotics can have spermatotoxin effects. In culture-positive patients, antibiotic therapy should be provided. In the more common, culture-negative patient, nonsteroidal antiinflammatory medications and frequent ejaculation are more appropriate. In refractory cases, sperm washing to remove white cells followed by IUI can be successful.
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