Diagnosis of Male Infertility
Given that a male factor can be identified as the cause of infertility in 30–40% of couples and is a contributing factor in 50% of cases, it is important to evaluate the male and female partners in parallel. Although infertility is defined as a failure to conceive after 1 year of unprotected sexual intercourse, couples may be anxious to proceed with an evaluation sooner and this may be appropriate. A complete urologic evaluation is important because male infertility may be the presenting symptom of otherwise occult but significant systemic disease. The evaluation involves collecting 4 types of information, as outlined in Figure 42–4.
History The cornerstone of the male partner evaluation is the history. It should note the duration of infertility, earlier pregnancies with present or past partners, and whether there was previous difficulty with conception. A comprehensive list of information relevant to the fertility history is given in Table 42–4. A sexual history should be addressed. Most men (80%) do not know how to precisely time intercourse to achieve a pregnancy. Since sperm reside within the cervical mucus and crypts for 1–2 days, an appropriate frequency of intercourse is every 2 days for most men. Lubricants can influence sperm motility and should be avoided. Commonly used products such as K-Y Jelly, Surgilube, Lubifax, most skin lotions, and saliva significantly reduce sperm motility in vitro. If needed, acceptable lubricants include vegetable, safflower, and peanut oils. A general medical and surgical history is also important. Any generalized insult such as a fever, viremia, or other acute infection can decrease testis function and semen quality. The effects of such insults are not noted in the semen until 2–3 months after the event, because spermatogenesis requires 75 days to complete. Surgical procedures on the bladder, retroperitoneum, or pelvis can also lead to infertility, by causing either retrograde ejaculation of sperm into the bladder or anejaculation (aspermia), in which the muscular function within the entire reproductive tract is inhibited. Hernia surgery can also result in vas deferens obstruction in 1% of cases; this incidence may be rising because of the recent increased use of mesh patches that tend to be inflammatory to tissues. Childhood diseases may also affect fertility. A history of mumps can be significant if the infection occurs postpubertally. After age 11, unilateral orchitis occurs in 30% of mumps infections and bilateral orchitis in 10%. Mumps orchitis is thought to cause pressure necrosis of testis tissue from viral edema. Marked testis atrophy is usually obvious later in life. Cryptorchidism is also associated with decreased sperm production. This is true for both unilateral and bilateral cases. Longitudinal studies of affected boys have shown that abnormally low sperm counts can be found in 30% of men with unilateral cryptorchidism and 50% of men with bilateral undescended testes. Differences in fertility have not been as easy to demonstrate, but it appears that boys with unilateral cryptorchidism have a slightly higher risk of infertility. However, only 50% of men with a history of bilateral undescended testes are fertile. It is important to remember that orchidopexy performed for this problem does not improve semen quality later in life. Exposure and medication histories are very relevant to fertility. Decreased sperm counts have been demonstrated in workers exposed to specific pesticides, thought to result from a shift in the normal testosterone/estrogen hormonal balance. Ionizing radiation is also a well-described exposure risk, with temporary reductions in sperm production seen at doses as low as 10 cGy. Several medications (Table 42–5) and ingestants such as tobacco, cocaine, and marijuana have all been implicated as gonadotoxins. The effects of these agents are usually reversible on withdrawal. Androgenic steroids, often taken by bodybuilders to increase muscle mass and development, act as contraceptives with respect to fertility. Excess testosterone inhibits the pituitary-gonadal hormone axis. The routine use of hot tubs or saunas should be discouraged, as these activities can elevate intratesticular temperature and impair sperm production. In general, a healthy body is the best reproductive body. The family and developmental histories may also provide clues about infertility. A family history of cystic fibrosis (CF), a condition associated with congenital absence of the vas deferens (CAVD), or intersex conditions is important. The existence of siblings with fertility problems may suggest that a Y chromosome microdeletion or a cytogenetic (karyotype) abnormality is present in the family. A history of delayed onset of puberty could suggest Kallmann or Klinefelter syndrome. A history of recurrent respiratory tract infections may suggest a ciliary defect characteristic of the immotile cilia syndromes. It is important to remember that reproductive technologies enable most men afflicted with such conditions to become fathers and therefore allow for the perpetuation of genetic abnormalities that may not be normally sustained. Physical Examination A complete examination of the infertile male is important to identify general health issues associated with infertility. For example, the patient should be adequately virilized; signs of decreased body hair or gynecomastia may suggest androgen deficiency. The scrotal contents should be carefully palpated with the patient standing. As it is often psychologically uncomfortable for young men to be examined, one helpful hint is to make the examination as efficient and as matter of fact as possible. Two features should be noted about the testis: size and consistency. Size is assessed by measuring the long axis and width; as an alternative, an orchidometer can be placed next to the testis for volume determination (Figure 42–5). Standard values of testis size have been reported for normal men and include a mean testis length of 4.6 cm (range 3.6–5.5 cm), a mean width of 2.6 cm (range 2.1–3.2 cm), and a mean volume of 18.6 mL (± 4.6 mL) (Figure 42–6). Consistency is more difficult to assess but can be described as firm (normal) or soft (abnormal). A smaller or softer than normal testis usually indicates impaired spermatogenesis.
The peritesticular area should also be examined. Irregularities of the epididymis, located posterior-lateral to the testis, include induration, tenderness, or cysts. The presence or absence of the scrotal vas deferens is critical to observe, as 2% of infertile men may present with CAVD. Engorgement of the pampiniform plexus of veins in the scrotum is indicative of a varicocele. Asymmetry of the spermatic cords is the usual initial observation, followed by the feeling of an "impulse" with increased intra-abdominal pressure associated with a Valsalva maneuver. Varicoceles are usually found on the left side (90%) and are commonly associated with atrophy of the left testis. A discrepancy in testis size between the right and left sides should alert the clinician to the possibility of varicocele. Prostate or penile abnormalities should also be noted. Penile abnormalities such as hypospadias, abnormal curvature, or phimosis could result in inadequate delivery of semen to the upper vaginal vault during intercourse. Prostatic infection may be detected by the finding of a boggy, tender prostate on rectal examination. Prostate cancer, often suspected with unusual firmness or a nodule within the prostate, can occasionally be diagnosed in infertile men. Enlarged seminal vesicles, indicative of ejaculatory duct obstruction, may also be palpable on rectal examination. Laboratory Laboratory testing is an important part of the male infertility evaluation. Urinalysis A urinalysis is a simple test that can be performed during the initial office visit. It may indicate the presence of infection, hematuria, glucosuria, or renal disease, and as such may suggest anatomic or medical problems within the urinary tract. Semen Analysis A carefully performed semen analysis is the primary source of information on sperm production and reproductive tract patency. However, it is not a measure of fertility. An abnormal semen analysis simply suggests the likelihood of decreased fertility. Studies have established that there are certain limits of adequacy below which it may be difficult to initiate a pregnancy. These semen analysis values were identified by the World Health Organization (1992) and are considered the minimum criteria for "normal" semen quality (Table 42–6). It is statistically more difficult to achieve a pregnancy if a semen parameter falls below any of those listed. Of these semen variables, the count and motility appear to correlate best with fertility. Semen Collection Semen quality can vary widely in a normal individual from day to day, and semen analysis results are very dependent on collection technique. For example, the period of sexual abstinence before sample collection is a large source of variability. With each day of abstinence (up to 1 week), semen volume can rise by up to 0.4 mL, and sperm concentration can increase by 10–15 million/mL. Sperm motility tends to fall when the abstinence period is longer than 7 days. For this reason, it is recommended that semen be collected after 48–72 h of sexual abstinence. To establish a baseline of semen quality, at least 2 semen samples are needed. Semen should be collected by self-stimulation, by coitus interruptus (less ideal), or with a special, nonspermicidal condom into a wide-mouthed, clean (not necessarily sterile) glass or plastic container. Because sperm motility decreases after ejaculation, it is important to have the specimen analyzed within 1 h of procurement. During transit, the specimen should be kept at body temperature. Physical Characteristics and Measured Variables Fresh semen is a coagulum that liquefies 5–30 min after ejaculation. After liquefaction, semen viscosity is measured and should not show any stranding. Ejaculate volume should be at least 1.5 mL, as smaller volumes may not sufficiently buffer against vaginal acidity. Low ejaculate volume may indicate retrograde ejaculation, ejaculatory duct obstruction, incomplete collection, or androgen deficiency. Sperm concentration should be > 20 million sperm/mL. Sperm motility is assessed in 2 ways: the fraction or percentage of all sperm that are moving and the quality of sperm movement (how fast, how straight they swim). A normal value for sperm motility is 50–60% motile and quality or progression score of at least 2 (on a scale of 0 [no movement] to 4 [excellent progression]). Sperm cytology or morphology is another measure of semen quality. By assessing the exact dimensions and shape characteristics of the sperm head, midpiece, and tail, sperm can be classified as "normal" or not. In the strictest classification system (Kruger morphology), only 14% of sperm in the entire ejaculate are truly normal looking. In fact, this number correlates with the success of egg fertilization in vitro and thus is ascribed real clinical significance. In addition, it is accepted that sperm morphology is a sensitive indicator of overall testicular health, because the sperm morphologic characteristics are determined during spermatogenesis. The role of sperm morphology assessment in the male infertility evaluation is to complement other information and to better estimate the chances of fertility. Computer-Assisted Semen Analysis (CASA) In an effort to remove the subjective variables inherent in the manual semen analysis, there have been attempts to quantify sperm motility, concentration, and morphology with computers. Computer-aided semen analyses couple video technology with digitalization and microchip processing to categorize sperm features by algorithms. Most commonly, CASA systems report sperm concentration, motilities, and velocities (curvilinear, straight-line) and can be used to analyze sperm shape by examination of nuclear features. Although the technology is promising, when manual semen analysis findings are compared with those from CASA on identical specimens, CASA can overestimate sperm counts by 30% in the presence of high levels of contaminating cells such as immature sperm or leukocytes. In addition, at high sperm concentrations, motility can be underestimated with CASA. At this point, CASA has accepted value in the research setting and is gaining further clinical acceptance. Seminal Fructose and Postejaculate Urinalysis Fructose is a carbohydrate derived from the seminal vesicles and is normally present in the ejaculate. If absent, the condition of seminal vesicle agenesis or obstruction may exist. Seminal fructose testing is indicated in men with low ejaculate volumes and no sperm. A postejaculate urinalysis is a microscopic inspection of the first voided urine after ejaculation for sperm. If sperm are found in the voided urine, then retrograde ejaculation is diagnosed. Such an analysis is indicated in diabetic patients with low semen volume and sperm counts; patients with a history of pelvic, bladder, or retroperitoneal surgery; and patients receiving medical therapy for prostatic enlargement. In general, the semen analyses of infertile men have patterns that may suggest a diagnosis (Table 42–7). Hormone Assessment An evaluation of the pituitary-gonadal axis can provide valuable information on the state of sperm production. In turn, it can reveal problems with the pituitary axis that can cause infertility (hyperprolactinemia, gonadotropin deficiency, congenital adrenal hyperplasia). It is recommended that FSH and testosterone levels be measured in infertile men with sperm densities of < 10 x 106 sperm/mL. Testosterone is a measure of overall endocrine balance. FSH reflects more on the state of sperm production rather than endocrine balance. This combination of tests will detect virtually all (99%) endocrine abnormalities (Sigman and Jarow, 1997). Serum LH and prolactin levels may be obtained if testosterone and FSH are abnormal, to help pinpoint the endocrine defect. Thyroid hormone, liver function, and other organ-specific tests should be obtained if there is clinical evidence of active disease, as uncontrolled systemic illnesses can affect sperm production. The common patterns of hormonal disorders observed in infertility are given in Table 42–8. With relatively normal spermatogenesis, low levels of plasma LH and FSH have no clinical meaning; likewise, an isolated low LH with normal testosterone is not significant. The measurement of plasma estradiol should be reserved for those men who appear underandrogenized or have gynecomastia in association with low, normal, or elevated testosterone levels. A large retrospective study on 1035 infertility patients examined the prevalence of endocrine disorders (Sigman and Jarow, 1997). On initial testing, 20% of infertile men had an abnormal hormone level, but only 9.6% of men harbored a true endocrinopathy on repeat testing. If FSH elevations are excluded, the incidence of clinically significant endocrinopathies in infertile men is 1.7%. In summary, the indications for hormonal evaluation of the infertile male are:
Adjunctive Tests Many adjunctive tests are available to help evaluate male-factor infertility if the initial evaluation fails to lead to a diagnosis. One guiding principle in this era of cost-containment is to order tests only if they will change patient management. Semen Leukocyte Analysis White blood cells (leukocytes) are present in all ejaculates and may play important roles in immune surveillance and clearance of abnormal sperm. Leukocytospermia or pyospermia, an increase in leukocytes in the ejaculate, is defined as > 1 x 106 leukocytes/mL semen and is a significant cause of male subfertility. The prevalence of pyospermia ranges from 2.8% to 23% of infertile men. In general, neutrophils predominate among inflammatory cells (Table 42–9). This condition is detected by a variety of diagnostic assays, including differential stains (eg, Papanicolaou), peroxidase stain that detects the peroxidase enzyme in neutrophils, and immunocytology. The reason for the immune cell infiltrate in pyospermia is poorly understood, although some proposed causes include an inflammatory response associated with infection, sensitization of the immune system to sperm antigens, or a reaction to low-grade toxins like cigarette smoke or alcohol. Antisperm Antibody Test The testis is a curious organ in that it is an immunologically privileged site, probably owing to the blood-testis barrier. Autoimmune infertility may occur when the blood-testis barrier is broken and the body is exposed to sperm antigens. Trauma to the testis and vasectomy are 2 common ways in which this occurs, giving rise to antisperm antibodies (ASA). ASA may be associated with impaired sperm transport through the reproductive tract or impairment in egg fertilization. An assay for ASA should be obtained when:
Antisperm antibodies can be found in 3 locations: serum, seminal plasma, and sperm-bound. Among these, sperm-bound antibodies are the most relevant. The antibody classes that appear to be clinically relevant include IgG and IgA. IgG antibody is derived from local production and from transudation from the bloodstream (1%). IgA is thought to be purely locally derived. Hypoosmotic Swelling Test The most clinically useful measure of sperm viability is cell motility. However, a lack of motility does not necessarily signify absent viability. Indeed, there are clinical conditions, such as immotile-cilia syndrome and extracted testicular sperm, in which there may be immotile but otherwise presumably healthy sperm. Such sperm can now be used clinically for micromanipulation and in vitro fertilization (IVF). Cell viability can be evaluated noninvasively by using the physiologic principle of hypoosmotic swelling. Conceptually, viable cells with functional membranes should swell when placed in a hypoosmotic environment (25 mM citrate and 75 mM fructose). Since sperm have tails, the swelling response is very obvious in that tail coiling accompanies head swelling. This sperm test is indicated in cases of complete absence of sperm motility. Sperm Penetration Assay (SPA) It is possible to measure the ability of human sperm to penetrate a specially prepared hamster egg in a laboratory setting. The hamster egg allows interspecies fertilization but no further development. This form of bioassay can give important information about the ability of sperm to undergo the capacitation process as well as penetrate and fertilize the egg. Infertile sperm would be expected to penetrate and fertilize a lower fraction of eggs than normal sperm. The indications for the diagnostic SPA are limited to situations in which functional information about sperm are needed, that is, to further evaluate couples with unexplained infertility and to help couples decide whether intrauterine insemination (IUI) (good SPA result) or IVF and micromanipulation (poor SPA result) is the appropriate next treatment. Sperm–Cervical Mucus Interaction Infertility can be caused by impaired sperm transport in the female reproductive tract. An evaluation of interaction between sperm and cervical mucus is one way to assess the quality of the transport process. One way to examine sperm-mucus interaction is by measuring the rate of sperm movement through a pool of cervical mucus on a microscope slide or within a capillary tube. This assay involves controls, in which sperm are placed in seminal fluid instead of cervical mucus. An abnormal cervical mucus–sperm interaction may suggest infertility treatment in which sperm are placed beyond the cervix into the uterus (IUI). Chromosomal Studies Subtle genetic abnormalities can present as male infertility. It is estimated that between 2% and 15% of infertile men with azoospermia (no sperm count) or severe oligospermia (low sperm counts) will harbor a chromosomal abnormality on either the sex chromosomes or autosomes. A blood test for cytogenetic analysis (karyotype) can determine if such a genetic anomaly is present. Patients at risk for abnormal cytogenetic findings include men with small, atrophic testes, elevated FSH values, and azoospermia. Klinefelter syndrome (XXY) is the most frequently detected sex chromosomal abnormality among infertile men (Figure 42–7).
Cystic Fibrosis Mutation Testing A blood test is indicated for infertile men who present with cystic fibrosis (CF) or the much more subtle condition, CAVD. Similar genetic mutations are found in both patients, although the former group is generally considered to have an atypical form of CF, in which the scrotal vas deferens is nonpalpable. Approximately 80% of men without palpable vasa will harbor a CF gene mutation. Recent data also indicate that azoospermic men with idiopathic obstruction and men with a clinical triad of chronic sinusitis, bronchiectasis, and obstructive azoospermia (Young syndrome) may be at higher risk for CF gene mutations. Y Chromosome Microdeletion Analysis As many as 7% of men with oligospermia and 15% of azoospermic men have small, underlying deletions in one or more gene regions on the long arm of the Y chromosome (Yq). Several regions of the Y chromosome have been implicated in spermatogenic failure, identified as AZFa, b, and c (Figure 42–8). Deletion of the DAZ (deleted in azoospermia) gene in the AZFc region is the most commonly observed microdeletion in infertile men. Fertility is possible in men with these deletions with IVF and micromanipulation of sperm. A polymerase chain reaction–based blood test can examine the Y chromosome from peripheral leukocytes for these gene deletions and is recommended for men with low or no sperm counts and small, atrophic testes.
Radiologic Testing Scrotal Ultrasound High-frequency (7.5–10 mHz) ultrasound of the scrotum has become a mainstay in the evaluation of testicular and scrotal lesions. In men who have a hydrocele within the tunica vaginalis space, the testis may be nonpalpable and should undergo ultrasound to confirm that it is normal. Any abnormality of the peritesticular region should also undergo a scrotal ultrasound to determine its characteristics or origin. Recently, scrotal color Doppler ultrasonography has been used to investigate varicoceles (Figure 42–9). By combining measurements of blood-flow patterns and vein size, both physiologic and anatomic information can be obtained for more accurate assessment. The diagnostic criteria that define a varicocele vary from study to study, but in general, a pampiniform venous diameter of > 2–3 mm is considered abnormal. Retrograde blood flow through the veins with a Valsalva maneuver is also an important radiologic feature of a varicocele.
Venography Venography is generally accepted as the most accurate way to diagnose varicoceles. Although found by palpation in approximately 30–40% of subfertile men, varicoceles can be detected by venography in 70% of patients. Renal and spermatic venography is fairly invasive and is usually performed through percutaneous cannulization of the internal jugular vein or common femoral vein. Venographically, a varicocele is defined by a Valsalva-induced, retrograde flow of contrast material from the renal vein into the scrotal pampiniform plexus. This test is expensive and technician-dependent; at present its main indications are to guide simultaneous percutaneous treatment of varicoceles or for the diagnosis of varicocele recurrence after prior treatment. Transrectal Ultrasound (TRUS) High-frequency (5–7 mHz) TRUS offers superb imaging of the prostate, seminal vesicles, and ejaculatory ducts. Transrectal ultrasound has virtually replaced surgical vasography in the diagnosis of obstructive lesions that cause infertility. Demonstration by TRUS of dilated seminal vesicles (> 1.5 cm in width) or dilated ejaculatory ducts (> 2.3 mm) in association with a cyst, calcification, or stones along the duct is highly suggestive of ejaculatory duct obstruction (Figure 42–10). In addition, prostatic abnormalities such as tumors and congenital anomalies of the vas, seminal vesicle, or ejaculatory ducts are easily defined. The indications for TRUS in infertility include low ejaculate volumes in association with azoospermia or severe oligospermia and decreased motility.
Computed Tomography Scan or Magnetic Resonance Imaging of the Pelvis The imaging techniques of CT and MRI can help define reproductive tract anatomy. However, since the advent of TRUS, these studies have relatively few indications. They include evaluation of a patient with a solitary right varicocele, a condition often associated with retroperitoneal pathology, and evaluation of the nonpalpable testis. Testis Biopsy & Vasography The testis biopsy is a useful adjunct in the infertility evaluation because it provides a more precise clinical diagnosis for several infertility disorders. Most commonly, the technique involves a small, open incision in the scrotal wall and testis tunica albuginea under local anesthesia. A small wedge of testis tissue is removed and examined histologically. Abnormalities of seminiferous tubule architecture and cellular composition can be assessed and categorized into several patterns. A testis biopsy is most useful in the azoospermic patient. It is often difficult to distinguish between a failure of sperm production and obstruction within the reproductive tract ducts in such patients. A testis biopsy allows delineation between these 2 conditions. In obstruction, formal investigation of the reproductive tract is warranted, beginning with a vasogram. A vasogram involves the injection of dye or contrast media into the vas deferens toward the bladder from the scrotum (Figure 42–11). In plain film radiographs, contrast material can delineate the proximal vas deferens, seminal vesicle, and ejaculatory duct anatomy and determine whether obstruction is present. Sampling of vasal fluid during the same procedure can also determine whether sperm exist within the scrotal vas deferens. Vasal sperm presence implies that there is no obstruction in the testis or epididymis. With this information, the site of obstruction can be accurately determined.
Whether a biopsy is indicated for oligospermia is controversial. Rare cases of partial reproductive tract obstruction may be diagnosed by biopsy, but the incidence of these disorders is low. While unilateral testis biopsies are usually sufficient, the finding of 2 asymmetric testes may warrant bilateral testis biopsies. This situation may reflect a unilateral unobstructed failing testis paired with a normal obstructed testis. Testis biopsies may also be indicated to identify patients at high risk for intratubular germ cell neoplasia. This premalignant condition exists in 5.5% of men with a contralateral germ cell tumor of the testis and is more prevalent in infertile than fertile men. A relatively new indication for the testis biopsy is to determine whether men with atrophic, failing testes and elevated FSH levels actually have mature sperm that may be used for IVF and intracytoplasmic sperm injection (ICSI). A single testis biopsy can detect the presence of sperm in 30% of men with azoospermia, elevated FSH levels, and atrophic testes. Testicular sperm that are harvested by biopsy are now routinely used to help men with severe male-factor infertility to achieve fatherhood. Fine-Needle Aspiration "Mapping" of Testes Although testicular sperm is used with IVF and ICSI to achieve pregnancies, there is a failure to obtain sperm in 25–50% of men with testis failure. When testis biopsies fail to retrieve sperm, IVF cycles are canceled at great emotional and financial cost. To minimize the chance of failed sperm retrieval, percutaneous fine-needle aspiration and "mapping" of the testis has been described (Figure 42–12). This technique can detect sperm in 60% of men with nonobstructed azoospermia and has confirmed that spermatogenesis can vary geographically in the failing testis such that "pockets" of sperm can exist.
Like a testis biopsy, fine-needle aspiration procedure is performed under local anesthesia. Percutaneously aspirated seminiferous tubules from various locations in the testis (5–10 mg) are smeared on a slide, fixed, stained, and read by a cytologist for the presence or absence of sperm. The information gained from this technique can fully inform patients of their chances of subsequent sperm retrieval for IVF and ICSI. Semen Culture Seminal fluid that passes through the urethra is routinely contaminated with bacteria. This can make the interpretation of semen culture difficult. Thus, semen cultures should not be obtained at random, but only in selected situations, given that 83% of all infertile men will have positive semen cultures and that the relationship between bacterial cultures and infertility is at best inconclusive. Semen cultures should be obtained when there are features suggestive of infection, including (1) a history of genital tract infection, (2) abnormal expressed prostatic secretion, (3) the presence of more than 1000 pathogenic bacteria per milliliter of semen, and (4) the presence of > 1 x 106 leukocytes per milliliter of semen (pyospermia). The agents most commonly responsible for male genital tract infections are listed in Table 42–10. Gonorrhea is the most common infection. Ten percent to 25% of chlamydial infections may be asymptomatic. Trichomonas vaginalis is a protozoan parasite responsible for 1–5% of nongonococcal infections; it is usually symptomatic. Ureaplasma urealyticum is a common inhabitant of the urethra in sexually active men (30–50% of normal men) and is responsible for one-fourth of all cases of nongonococcal infections. Escherichia coli infections are relatively uncommon in young men and are usually symptomatic. Mycoplasmas are aerobic bacteria that are known to colonize the male reproductive tract. Rarer but possible causes of infection include anaerobic bacteria and tuberculosis. |
