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figure a

Interpretation of semen analysis (SA) results is an important skill for any clinician who cares for men with subfertility or testicular dysfunction. Confirmed SA abnormalities indicate the presence of male factor infertility, which occurs in 40–60% of subfertile couples, and guides subsequent evaluation and management. Male factor infertility is important to identify because it may be amenable to medical or surgical therapy, and because it may be the presenting symptom of occult health-threatening conditions such as hypogonadism or testicular cancer. Moreover, some causes of severe male factor infertility such as Y chromosome microdeletions and ­chromosomal translocations are ­genetically transmissible and may threaten the health or fertility of the patient’s potential offspring. Semen analysis should be performed according to standard protocol published by the World Health Organization (WHO). Each sample should be collected after an ejaculatory abstinence period of 2–5 days. Samples should be collected in wide-mouthed, sterile containers, maintained as close as possible to body temperature, and analyzed within 1 h. 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 (sperm per mL), total sperm number (sperm per total ejaculate), sperm motility (% of sperm with any motility and % of sperm with forward progressive motility), and sperm morphology (% of morphologically normal sperm). Abnormalities of semen parameters are typically described using standard nomenclature (Table 1.1) based upon reference values published by the WHO (Table 1.2).

Table 1.1 Semen analysis nomenclature
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Table 1.2 Semen analysis reference limits published by the World Health Organization in 1999 and 2010
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(A)

In 1999 and 2010 the WHO published the only widely used, accepted reference limits for interpretation of the semen analysis (Table 1.2). It is important to understand that the WHO reference limits do not reflect “normal” or “average” values and do not have a validated relationship with subfertility. The 1999 reference limits were the result of expert consensus, while the 2010 reference limits were defined as the statistical 5th percentile value for each SA parameter derived from an international population of fertile men. The WHO reference limits should not be used as strict criteria to define the presence or absence of male factor subfertility, but rather should serve as a useful guide during the evaluation of each individual patient. Correctable male factors may be present in some men whose semen parameters are within the WHO 2010 normal ­reference range, and such men may benefit from treatment.

(B)

The initial evaluation of men with an abnormal semen analysis should include a detailed medical history (Table 1.3), a directed physical examination (Table 1.4), and measurement of serum testosterone (T), and follicle stimulating hormone (FSH). The serum T and FSH levels may indicate the presence of medically important and treatable endocrine dysfunction. FSH is a crude but reasonable marker of the level of spermatogenesis. The higher the level the more likely spermatogenesis is impaired. FSH levels higher than 8 IU/L are concerning for primary testicular dysfunction.

Table 1.3 Important points to elicit in the medical history of patients with an abnormal semen analysis
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Table 1.4 Important points during physical examination of patients with an abnormal semen analysis
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(C)

Significant intra-individual variation in semen parameters is common and at least two semen samples should be analyzed for each patient. It is preferable that the samples are collected over more than 1 cycle of spermatogenesis (2 months apart), particularly if systemic illness or gonadotoxin exposure has occurred. Analysis of a third semen sample may be informative if significant discrepancy exists between the two samples.

(D)

Some semen analysis abnormalities indicate the possibility of specific underlying etiologies and warrant-specific diagnostic testing and clinical management. These abnormalities include azoospermia, low semen volume, globozoospermia, absolute asthenozoospermia, and severe oligozoospermia (sperm concentration <5 million per mL, isolated or in combination with other semen analysis abnormalities).

(E)

Globozoospermia refers to the very rare (<1 in 1,000 semen analyses) condition in which all sperm are round-headed due to absence of the acrosome. Globozoospermia is easily diagnosed by an experienced andrologist during standard light microscopic evaluation, and may be confirmed if desired by sperm electron microscopy. Fertilization and biological paternity are only possible by intracytoplasmic sperm injection (ICSI), which is thought to be safe but is only effective in some cases.

(F)

Absolute asthenozoospermia refers to the rare condition (1 in 5,000 semen analyses) in which 100% of sperm in freshly ejaculated semen are immotile. This finding indicates one of the three possible underlying conditions: live sperm that are immotile because of ultrastructural flagellar defects, live sperm with unexplained (idiopathic) immotility, and dead sperm (necrozoospermia). The group of patients with ultrastructural defects includes patients with immotile-cilia syndrome and Kartagener’s syndrome (immotile cilia syndrome plus situs inversus). The first step in the evaluation of absolute asthenozoospermia is to search for correctable factors such as genital tract infections, latex condom exposure, prolonged abstinence from ejaculation, and more rare conditions such as partial ejaculatory duct obstruction. If no correctable factors are identified, or if the condition persists after the correctable factor is addressed, the next step is semen processing by centrifugation, density gradient sperm selection, sperm incubation, and extensive sperm search. Identification of any motile sperm obviates the need for further specific testing, and the patient should be evaluated as is suggested for patients with “global or non-specific abnormalities.” Sperm viability testing is indicated if motile sperm cannot be identified after semen processing. The commonly used sperm viability assays test sperm membrane function and include the eosin-nigrosin test (live sperm exclude the red eosin dye whereas dead sperm do not) and the hypo-osmotic swelling test (live sperm swell when placed in hypo-osmotic solution whereas dead sperm do not). Sperm electron microscopy may be considered (if available) to evaluate for sperm ultrastructural defects when viable sperm are found. In such cases, reproduction is possible by ICSI, which may be optimized by use of sperm selection techniques to identify viable sperm for oocyte microinjection. Genetic counseling is recommended to inform the patient of the risks of absolute asthenozoospermia, infertility, and associated health problems (such as recurrent pulmonary infections due to immotile cilia syndrome) in potential offspring. If no viable sperm are found, the diagnosis is necrozoospermia. This condition may result from sperm death that occurs in the testis or epididymis due to infection, oxidative stress, hyperthermia, gonadotoxin exposure, systemic illnesses, or sometimes advancing age. In some cases viable sperm may be surgically retrieved from the testis and used for ICSI.

(G)

Y chromosome microdeletion testing and peripheral blood karyotyping are indicated in all men with severe oligozoospermia (i.e., sperm concentrations <5 million/mL). Genetic defects are detectable in 10–15% of such patients and are important to identify because of their prognostic relevance, possible overall health implications, and in some cases transmissibility to conceived offspring. The most commonly detected abnormalities in this population are Y chromosome microdeletions involving a region of the Y chromosome known as the AZFc (azoospermic factor C) region. Complete or partial AZFc deletions have variable effects on sperm production that range from severe oligozoospermia to azoospermia, and have no other known clinical sequelae. Diagnosis enables genetic counseling prior to assisted reproduction, which is critical because Y chromosome microdeletions are transmitted to all male offspring who inherit the abnormal Y chromosome. Other genetic abnormalities detected in severely oligozoospermic men include sex chromosome abnormalities (particularly classic or mosaic Klinefelter’s syndrome, 47,XXY or 46,XY/47,XXY) and autosomal anomalies such as translocations and inversions. Patients with any karyotype abnormalities should undergo genetic counseling prior to assisted reproduction. Pre-implantation genetic diagnosis is indicated in some cases to reduce the risk of aneuploidy in offspring.

(H)

Assisted reproduction may be the only option for achievement of biological paternity for men with severe deficits in semen quality. ICSI is an advanced reproductive technology during which a single sperm is directly injected into a single oocyte under microscopic guidance. ICSI is an alternative to conventional in vitro fertilization, during which thousands of sperm are placed in the oocyte’s microenvironment (together in a Petri dish) but must fertilize the oocyte without assistance. The development of ICSI in the early 1990s revolutionized the treatment of severe male factor infertility by enabling successful reproduction with surgically retrieved testicular sperm or functionally impaired ejaculated sperm.

(I)

The majority of subfertile men exhibit mild to moderate abnormalities in one or more semen analysis parameters and can generally be evaluated with the same diagnostic algorithm. This includes patients with isolated or combined oligozoospermia, teratozoospermia, and asthenozoopsermia (absolute asthenozoospermia and globozoospermia, however, require more specific evaluation, see “E” and “F”).

(J)

Additional testing is helpful in some cases of poor semen quality and should be directed by the initial evaluation (history, physical examination, serum T, serum FSH, semen analysis). The goal of additional diagnostic testing is to identify or confirm the presence of treatable male factors that are not readily apparent from the initial evaluation. Indications for commonly used tests and methods for interpretation of their results are presented in Table 1.5.

Table 1.5 Explanation of adjunctive tests useful in the evaluation of abnormal semen analysis
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(K)

Testing for anti-sperm antibodies should be considered when isolated asthenozoospermia or sperm agglutination (microscopic attachment of motile sperm to one another) are present on semen analysis. Anti-sperm antibodies can inhibit sperm transit through the female reproductive system and may interfere with sperm survival and/or oocyte fertilization. The most clinically important assays examine semen for the presence of antibodies bound to sperm. The clinical significance of serum anti-sperm antibodies in the male is less clear. Some experts advocate treatment of anti-sperm antibodies with systemic corticosteroids. Described protocols include cycled treatment with 40–80 mg of daily methylprednisolone on menstrual cycle days 1–10, and continuous treatment with 2–3 mg of daily dexamethasone for 9–13 weeks. However, this approach has not been prospectively validated and patients must be warned about the rare but serious side effect of aseptic bone necrosis. Other experts advocate treatment of affected subfertile couples with ICSI, which is not significantly affected by anti-sperm antibodies.

(L)

Infections of the male genital tract may have significant adverse effects on semen quality or sperm function. Although the value of antimicrobial testing in asymptomatic subfertile men is controversial and not supported by robust evidence, many experts advocate treating any positive cultures that are detected. The goals of therapy are to resolve any symptoms of infection that are present, to ameliorate the theoretical adverse effects of infection on semen quality and sperm function, and to avoid transmission of infection to the female partner.

(M)

Varicocele refers to the presence of abnormally dilated spermatic cord veins and is the most common correctable cause of male subfertility, found in 35–40% of cases. A large body of evidence that includes several meta-analyses and randomized controlled prospective trials has shown that varicocele has a negative impact on male fertility, and that varicocele treatment improves both semen quality and pregnancy outcomes. Nonetheless, considerable controversy persists about the value of varicocele treatment due to significant methodological flaws in most of the existing literature. The American Urological Association and the American Society for Reproductive Medicine advocate varicocele treatment in men with palpable varicoceles, impaired semen quality, and documented ­subfertility, who have a female partner with ­normal fertility or correctable infertility. The best treatment modality is microsurgical varicocelectomy, which has lower recurrence and complication rates and yields greater improvements in semen quality than radiographic embolization or non-microsurgical surgical ligation.

(N)

Treatable endocrine abnormalities are the cause of only a small percentage of male subfertility cases. In most cases, treatment of the endocrine abnormality yields significant improvements in semen quality and often enables unassisted conception. Hypogonadotropic hypogonadism may be treated with gonadotropin replacement therapy. Deficiences in LH can be corrected by administration of human chorionic gonadotropin (hCG) injections (1,000–3,000 IU IM or subcutaneously three times per week). FSH deficiency is treated with injectable recombinant FSH (100–150 U three times per week). Treatment is typically highly effective but often requires prolonged gonadotropin replacement. Prolactin secreting pituitary tumors may be treated medically (Carbegoline 0.125–1.0 mg twice weekly) or surgically. Finally, although endocrine therapy is largely ineffective for primary testicular failure, patients with abnormally low (<10) serum testoserone:estradiol ratios may benefit from treatment with an aromatase inhibitor (anastrazole 1 mg daily, testalactone 100–200 mg daily, or letrazole 2.5 mg daily).

(O)

High dietary intake of fruits, vegetables, and whole grains has been recently linked to improve sperm function; and high intake of meat and potatoes may be associated with higher sperm concentrations. Chronic heavy alcohol use can impair the hypothalamic-pituitary axis, and acute alcohol ingestion directly interferes with sperm morphology. Moderate or social alcohol ingestion, however, is not associated with male subfertility. Cigarette smoking and marijuana smoking have been consistently associated with low sperm concentration, low motility, and poor morphology. Chronic scrotal heat exposure, most commonly including frequent use of hot tubs or saunas, impairs testicular function. Medications that may adversely affect semen quality are listed in Table 1.6.

Table 1.6 Medications associated with male infertility
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(P)

Empiric therapy for male subfertility is advocated by some experts when no modifiable male factors are present. Although such treatments are supported only by limited evidence, semen quality and reproductive outcomes may improve significantly in appropriately selected patients. Antioxidant therapy and estrogen receptor modulation are the two most commonly utilized strategies. Oral antioxidants for which at least one study has demonstrated a benefit include coenzyme Q, vitamins C and E, carnitine, glutathione, N-acetylcysteine, and selenium. Clomiphene citrate (CC) is the most commonly used estrogen receptor modulator, which is used to drive testicular function by decreasing negative feedback exerted by ­estradiol at the pituitary, thereby increasing gonadotropin production. Due to its mechanism of action, CC is thought to work best in patients with low to normal serum LH levels.