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HWG Baker MD PhD FRACP,  Professor, University of Melbourne Department of Obstetrics and Gynaecology, The Royal Women's Hospital, Parkville 3052 Victoria
Australia

Updated December 2008

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NATURE AND CAUSES OF MALE INFERTILITY DEFINITIONS

Infertility is the inability to produce a pregnancy or failure to do so within a reasonable period of trying, usually 6 to 12 months. Sterility is a total inability to produce a pregnancy, and this may be reversible or irreversible. Subfertility is infertility without an absolute barrier to reproduction that would cause sterility, such as azoospermia. Hypogonadism is a nonspecific term for decreased testicular or ovarian function that could include a disorder of gamete production or function or a disorder of sex hormone production or action. Usually male hypogonadism indicates testicular failure associated with androgen deficiency. Primary hypogonadism results from disorders that affect the gonads directly, and secondary hypogonadism results from defective pituitary gonadotropin secretion.

INCIDENCE AND DISTRIBUTION

Of couples planning a pregnancy up to 50% conceive in the first cycle and in the remainder, the percentage who conceive in each successive month declines as the proportion of subfertile couples left continuing to try increases. Approximately 85% conceive a first pregnancy by 6 to 12 months.^1-3 The 6- to 12-month period used to define infertility means that it afflicts approximately 15% of couples.⁴ Infertility is thus common and the male contribution is substantial.⁵ Infertility results from female disorders (anovulation, tubal obstruction, or other pathology) in approximately 30%, a male disorder in 30%, and disorders in both partners in 30%. No abnormalities are found in approximately 10%. Because male and female factors frequently coexist, both partners of the infertile couple are investigated and managed together.⁶

ETIOLOGY AND CLASSIFICATION OF MALE INFERTILITY

At present, the precise cause cannot be determined in most men investigated for infertility.^{6, 7} Relationships between testicular damage, semen quality, and fertility are not strong.^8-10 Even genetic disorders may have marked phenotypic variation. For example, with microdeletions in the long arm of the Y chromosome, testicular histology may show Sertoli-cell-only syndrome, germ cell arrest, or hypospermatogenesis.^{11, 12} There are many hypotheses for the causes of the common forms of male infertility, including minor hormonal disturbances, dietary deficiencies of vitamins and minerals, disturbed scrotal thermoregulation with or without varicocele and accessory sex gland inflammation.¹³ Currently the testicular dysgenesis syndrome and reactive oxygen species (ROS) damage are topical (see chapter by Giwercman and Giwercman).^{14, 15} The concept of the testicular dysgenesis syndrome arose from concerns that toxins in the environment, acting in concert with genetic predisposition, are affecting testicular development. It encompasses hormonal inhibition ("endocrine disruption") of the proliferation of Sertoli cell precursors, Leydig cells and germ cells during fetal life via adverse environmental, dietary, lifestyle or other influences affecting the mother and resulting in increased risks of cryptorchidism, hypospadias, primary spermatogenic defects, and testicular cancer.¹⁴ ROS are believed to be causal in the relationship between abnormal spermatozoa in semen, DNA strand breaks in sperm heads and markers of apoptosis in sperm.¹⁵ The importance of these pathogenetic mechanisms in male infertility remains to be determined.^{16, 17}

A classification of causes of male infertility based on the effectiveness of treatment is shown in Table 1. In this classification, effective treatment means medical intervention known or proved by clinical trial to improve the chances of the man producing a conception by coitus or artificial insemination and does not include the use of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) to bypass the impairment.

CLINICAL EVALUATION

Patients with irreversible sterility can be separated from those with potentially treatable conditions or subfertility usually by standard clinical evaluation (Table 2) and some simple investigations (Table 3).

HISTORY

It cannot be overemphasized that both members of the couple need to be involved in the assessment and discussion of the results. The emotional reaction of the couple to the diagnosis of infertility may interfere with clinical evaluation and management. Intimate information may not be disclosed while the couple is embarrassed, hostile, or confused. Previous sexually transmissible infections or pregnancy may be concealed from the partner.

Nature and Duration of Infertility

Previous pregnancies and time taken to conceive each pregnancy and duration of infertility are important prognostic factors. The couple may be aware of an infertility-related problem, such as previous undescended testes or orchitis. Some who present with a short duration of infertility may be unaware of the normal human pregnancy rates. The plan for investigation depends on the possibility of finding remediable abnormalities and on the age of the female partner.Family

History
The family history should be considered but may not be known because infertility is often not discussed openly.^{18, 19} Increasing numbers of chromosomal and genetic causes for male infertility are being discovered (Table 4).^20-22 Some of these cause sterility and are recessive disorders or de novo mutations. Others may only affect fertility slightly so that there may be no family history of infertility. The most important include Kallmann’s syndrome, myotonic dystrophy, androgen receptor defects, gonadotropin and gonadotropin receptor defects, cystic fibrosis and bilateral congenital absence of the vasa, and chromosomal rearrangements / aneuploides and Yq microdeletions.^{11, 12, 20, 23-30} However, collectively they explain less than 10% of male infertility.There are many pediatric syndromes that involve hypogonadism or undescended testes in association with ambiguous genitalia, multiple malformations, obesity, or mental retardation, but patients with these generally do not present for management of infertility. Other genetic diseases may be associated with infertility, for example, congenital adrenal hyperplasia, hemoglobinopathy, Huntington’s disease, polycystic kidneys, and mitochondrial disorders.^{20, 31-34} Predispositions to some conditions may also have a genetic basis such as the anatomic variant of the tunica vaginalis which predisposes to testicular torsion, the association of Young’s syndrome with mercury poisoning in infancy and the familial aspects of sperm autoimmunity. Men with sperm autoimmunity have increased frequencies of both family histories of organ-specific autoimmune diseases and autoantibodies to thyroid and gastric parietal cells in their serum.³⁵ Furthermore, brothers of men with poor semen analysis results are more often infertile than expected.^{18, 19} Thus, it is postulated that genetic causes or predispositions will be found for most male infertility. However, genetic factors remain unclear for the common types or associations of male infertility: idiopathic oligospermia, asthenospermia, teratospermia and undescended testes.

Coital Adequacy and Timing

Information on impotence and ejaculatory disturbances is important because intravaginal deposition of semen near the time of ovulation is crucial for fertility. Infrequent coitus is common in couples seen for infertility. Low libido may result from androgen deficiency, general illness, or a psychological reaction to the infertility.

Childhood and Pubertal Development

Treatment in childhood for penile or scrotal disorders (e.g., hypospadias, epispadias, urethral valves, undescended testes, inguinal hernia, hydroceles) could be relevant (see chapter by Hutson). Sexual maturation may be delayed and incomplete with primary or secondary hypogonadism. There may have been associated growth problems that required treatment. Early puberty and growth resulting in short stature suggest congenital adrenal hyperplasia.^{31, 32}

General Health

Any illness, acute or chronic, can impair sperm production in a nonspecific manner.³⁶ Acute critical illness, such as severe trauma, surgery, myocardial infarction, burns, liver failure, intoxication, and starvation, is often accompanied by suppression of gonadotropin secretion and secondary hypogonadism. In contrast, a primary testicular disorder with elevated gonadotropin levels may occur with chronic illnesses. Increased peripheral conversion of androgens to estrogens may produce some features of feminization such as gynecomastia. The association of hypogonadism and feminization with chronic liver disease is well known. Similar hypogonadism may occur with other chronic illnesses such as chronic anemia, chronic renal failure, rheumatoid arthritis, chronic spinal cord injury, thyroid diseases, Cushing’s syndrome, obesity, human immunodeficiency virus (HIV) infection, and neoplasia. Sex hormone–binding globulin levels are increased with some conditions such as cirrhosis and thyrotoxicosis but suppressed with others such as obesity, hypercortisolism, and hypothyroidism.³⁶ Numerous drugs have side effects on the reproductive system.³⁶ Heroin addiction and intrathecal narcotic infusions to control chronic pain suppress luteinizing hormone secretion.³⁷ Fever can cause transient declines of a few months’ duration.^{36, 38, 39} Diabetes mellitus may be associated with impotence in early uncontrolled stages, ejaculatory disorders with autonomic neuropathy, sperm autoimmunity and ROS damaged sperm.⁴⁰ Men with renal disease may have infertility of multifactorial origin, including testicular failure from chronic illness, cytotoxic drug exposure, zinc deficiency, and damage to the vasa or penile blood supply during kidney transplantation. However, as with cirrhosis, provided that metabolic decompensation is not severe, semen quality often is adequate for fertility.³⁶ Epididymal obstruction associated with chronic sinopulmonary disease (Young’s syndrome) was diagnosed frequently in Australia and the United Kingdom in the past yet is rare elsewhere.⁴¹ Some cases of Young’s syndrome may have been caused by mercury poisoning in childhood from calomel-containing teething powders.⁴² These were withdrawn from the market in the mid-1950s when it was found that they caused pink disease, and Young’s syndrome is seen less commonly. Bronchiectasis and sinusitis are common in men with immotile sperm from cilial defects.⁴³ Situs inversus may also be present.

Testicular Symptoms

Previously undescended testes are common in men being investigated for infertility.^{7, 44, 45} Undescended testes may be associated with other congenital malformations and disorders of testicular hormone production or action during fetal development, such as Kallmann’s syndrome, insulin-like factor 3 receptor mutations, androgen receptor mutations or defects of androgen metabolism, and diethylstilbestrol exposure in utero. In Western countries, this condition is usually treated in early childhood, but whether early surgery reduces the severity of the subsequent spermatogenic disorder is unclear. A testicular dystrophy may cause both the failure of descent and defective sperm production in adult life despite early surgery. It is difficult to explain otherwise how men with unilateral undescended testes are so frequent in the infertile population. Bilateral undescended testes carry a poorer outlook for fertility than unilateral undescended testes. Infertility after bilateral orchiopexy is approximately six times more common than in the general population and occurs in approximately half of the men, whereas after unilateral orchiopexy, infertility is increased by a factor of two and affects approximately 10%.⁴⁴ There may be associated malformation of the epididymides.⁴⁶ Rarely the testes may atrophy after surgery because of interference with the blood supply or coincidental torsion.

Episodes of severe testicular pain and swelling may result from torsion, orchitis, or epididymo-orchitis and may be followed by loss or atrophy of the testis. Post-inflammatory atrophy is particularly frequent with mumps orchitis but rare with other illnesses such as glandular fever and brucellosis.⁴⁷ Epididymo-orchitis of bacterial origin is commonly associated with urethritis or urinary tract infections and may follow straining with heavy lifting. Sexually transmitted diseases are important, particularly if there was associated epididymal pain or swelling. Some patients have post-gonococcal obstructions in the tails of the epididymides without clear or admitted histories of epididymitis.

Failure of development and a decrease in size of one or both testes are important symptoms of spermatogenic defects. Torsion of the testes may cause atrophy. The vasa may be damaged during hernia repairs and kidney transplantation. Testicular biopsy may inadvertently damage the epididymis, especially if retroversion of the testis is not recognized and the biopsy is performed without taking the testis out of the tunica. Similarly, surgery for torsion, hydroceles, or epididymal cysts may result in the obstruction of the epididymis. Hematomas in the scrotum and infarction of the testes may follow interference with the vascular supply of the testes. Rarely, autoimmune orchitis results from testicular injury or inflammation. Testicular tumors and carcinoma in situ occur with increased frequency in infertile men, even without a history of undescended testes.^{14, 48}

Iatrogenic Infertility

Vasectomy and Sertoli-cell-only syndrome caused by cytotoxic chemotherapy and radiation therapy for malignant tumors of the testes, leukemia, lymphoma, and serious autoimmune diseases are the most common forms of medically induced infertility.^{49, 50} Although some treatment regimens only suppress spermatogenesis temporarily, recovery of fertility is unpredictable. Alkylating agents, such as cyclophosphamide and busulfan, destroy spermatogonia.⁵⁰ Antimetabolites may be used to treat psoriasis, rheumatoid arthritis, or xenograft rejection and can have transient adverse effects on spermatogenesis.^{36, 51} Treatment with sulfasalazine for inflammatory bowel disease or arthritis causes a reversible impairment of semen quality.³⁶ Cessation of sulfasalazine often results in a marked improvement in semen quality over several months. Many other drugs have real or potential adverse effects on spermatogenesis or sexual performance, including androgens, anabolic agents, estrogens, glucocorticoids, cimetidine, spironolactone, antibacterials (especially nitrofurantoin), antihypertensive drugs, and psychotropic agents. However, in practice these are not common causes of infertility.³⁶

Antispermatogenic Factors

Occupational and environmental exposures may affect reproduction.^{52, 53} Exposure to heat from frequent sauna baths, vehicle driving, furnaces, and perhaps working outdoors in summer may cause a decline in spermatogenesis. Impaired testicular heat exchange from obesity and varicoceles may accentuate the effect. Exposure to chemicals in the workplace or elsewhere, particularly nematocides; organophosphates; estrogens; benzene; and welding, zinc, lead, cadmium, and mercury fumes, may have antispermatogenic effects. Various social drugs, including tobacco, alcohol, marijuana, and narcotics, are potentially antispermatogenic, but these usually require heavy use for an adverse effect.^{36, 54, 55} Some addicts have other organ damage, such as cirrhosis, which may further impair testicular function.³⁶

PHYSICAL EXAMINATION

A general physical examination is performed (see Table 2) and specific abnormalities are sought in particular circumstances, for example, of the respiratory system with suspected genital tract obstructions or immotile sperm, the prostate for ejaculatory duct obstruction or prostatitis, the endocrine system for hypopituitarism or other defects associated with testicular failure, the nervous system for autonomic neuropathy with coital disorders, optic field defects with pituitary tumors, and hyposmia with Kallmann’s syndrome.

Virilization

Hair distribution varies markedly between men. The loss or reduced growth of facial, pubic, axillary, and body hair is an important feature of androgen deficiency but is often unrecognized by patients. Men may note a reduced frequency of the need to shave. The stages of genital and pubic hair development can be recorded according to the method of Tanner. Eunuchoidal proportions (arm span greater than 6 cm longer than height or pubis-to-floor measurement greater than 6 cm longer than one half the height) result from delayed fusion of the epiphyses and are a sign of delayed or incomplete puberty in whites or Asians but can be found with normal testicular function.

Gynecomastia

Gynecomastia of mild degree is common in men with testicular failure of any cause.³⁶ Marked gynecomastia may be associated with Klinefelter’s syndrome, cirrhosis, androgen receptor defects, estrogen-producing tumors, or anabolic steroid and human chorionic gonadotropin abuse. Galactorrhea is rare in men and usually but not always associated with hyperprolactinemia.⁵⁶

External Genitalia

Examination of the penis for the position of the meatus, phimosis, urethral strictures, and Peyronie’s disease is important because these may influence the adequacy or completeness of ejaculation. Inadequate penile size appears to be an exceptionally rare cause of infertility.⁵⁷

Examination of the scrotal contents is critical in the evaluation of male infertility. A general approach to the examination is outlined in Figure 172-1. The body of the testes, the head, the body, and the tail of the epididymis and vas are palpated on both sides as shown. Sometimes it is difficult to examine the scrotum thoroughly because of ticklishness or because the scrotum is very tight. Testes may retract into the superficial inguinal region, especially if small. Testes not present in the scrotum may be palpable in the subcutaneous tissue in the groin or, occasionally, in the inguinal canal. Palpable remnants of the vas and epididymis in the scrotum suggest the testis has atrophied completely—the vanishing testis.⁵⁸

Orchiometry

The volume of the testis is determined by comparison with an orchiometer (normal: 15–35 mL).⁵⁹ In the absence of varicoceles, the right and left testes are approximately equal in size. Testicular volume is related to body size and number of sperm per ejaculate. As seminiferous tubules occupy more than 90% of the volume of the testes, impairment of spermatogenesis is commonly associated with reduced testicular size. Testicular atrophy suggests severe impairment of spermatogenesis.

Testicular Abnormalities

Pain on palpation or excessive tenderness suggests inflammation. Loss of normal testicular sensation may occur with chronic inflammations, neuropathy, or neoplasia. Reduced consistency or softness of the testes is a feature of reduced spermatogenesis. Abnormalities of shape and hard lumps suggest tumors or scars.

Epididymal Abnormalities

Palpable abnormalities include congenital absence of the vas or other failures of development, enlargements of the heads or nodules in the tails of the epididymides with obstruction, spermatoceles, and other cysts and tumors. In men with very small testes (<5 mL), small epididymides suggest severe androgen deficiency, and normal-size epididymides suggest postpubertal testicular atrophy or a severe seminiferous epithelial disorder, such as Klinefelter’s syndrome.

Vasal Abnormalities

Abnormalities of the vas include absence, nodules and gaps with vasectomy, and thickening or beading of the vas with severe postinflammatory scarring as from tuberculosis.

Miscellaneous Abnormalities

Incidental scrotal findings include scars from surgery, scrotal dermatitis, and pubic fat pads around the genitals in extreme obesity. Inguinal hernias and lipomas and encysted hydroceles of the cord are palpated above and behind the epididymis. Cysts "hydatids" of the appendix testis or epididymis are typically anterior to the head of the epididymis. Spermatoceles and cysts of the paradidymis are in the head or body of the epididymis. Retroversion of the testes is common where the vas and epididymis are anterior rather than posterior to the testes. Hydroceles of mild degree are common. A tense hydrocele may hide a testicular tumor. Unilateral absence of the vas may be associated with ipsilateral agenesis of the kidney and ureter on the same side. Many of these anomalies have little relationship with infertility.

Checking for Varicocele

With the man standing up, the scrotum can be inspected for swelling of the pampiniform plexus and a cough or Valsalva impulse seen or palpated by holding the spermatic cords between the thumb and index finger of each hand and elevating the testes toward the external inguinal ring. This maneuver reduces the risk of confusing contractions of the cremaster muscles with venous impulses. Varicocele size is graded: cough impulse without palpable enlargement of the spermatic cord (grade 1), palpable enlargement (grade 2), and visible enlargement (grade 3). Although predominantly a left-sided condition, varicoceles may occasionally be on the right side.

The accuracy and reproducibility of clinical examination, even for structures as accessible as those in the scrotum, may not be high. Varicoceles may vary in size from day to day. Even absence of the vasa may be overlooked. With practice, orchiometry can be repeated to within one orchiometer size.

SEMEN ANALYSIS AND OTHER INVESTIGATIONS

Investigations are outlined in Table 3.

SEMEN ANALYSIS

The most important laboratory investigation in male infertility is semen analysis. The variables assessed and the methods are in the World Health Organization’s laboratory manual.⁶⁰ A new edition is due in 2008. Automation of semen analysis is in progress and should be used in most specialized laboratories soon.¹⁰

It is crucial that the laboratory is experienced in the performance of semen analyses, and participates in quality assurance activities.⁶¹ There should be a room nearby for the collection of semen. Semen may be obtained by masturbation or coitus using a special nontoxic condom. Ordinary latex contraceptive condoms are unsatisfactory because the rubber usually immobilizes the sperm.⁶² If these methods of collection are not possible, postcoital examination of midcycle cervical mucus may give some information about the likelihood of adequate semen quality if many motile sperm are found. In contrast, a negative postcoital test on its own is of little diagnostic value because conception can occur in the same cycle.⁶³

The man should be provided with a wide-mouth, sterile, and nontoxic collection jar and written instructions about collection and delivery to the laboratory. A period of abstinence from ejaculation from 2 to 5 days, delivery of the sample to the laboratory within 1 hour of collection, and avoidance of exposure to lubricants or extremes of temperature are specified.

Because of the variability of results, several semen analyses at intervals of 2 or more weeks are necessary in a man with an abnormality in the first test. Even with complete collection of samples, there is variability caused by counting error, other technical errors, and differences in the ejaculate from day to day (Fig. 2).^{60, 64} These large variations need to be remembered when interpreting results of semen analysis.

To check for retrograde ejaculation, urine collected immediately after ejaculation is centrifuged and the pellet examined for sperm.

Assays of semen constituents from the accessory glands and testis are available: zinc and acid phosphatase from the prostate, fructose from the seminal vesicles, neutral -glucosidase, glycerophosphocholine, and l-carnitine from the epididymis and inhibin B from the Sertoli cells. Prostatic fluid is acid (pH approximately 6.0), but the ejaculate is alkaline because of the admixture with seminal vesicle fluid. Semen biochemistry is of limited usefulness in clinical practice. Some examples are given in Table 5.

Immunobead Test

Tests for sperm antibodies should be done routinely on all men being evaluated for infertility because no semen analysis pattern is characteristic of sperm autoimmunity.^{35, 60} The immunobead test (IBT) with beads binding to more than 50% of motile sperm is regarded as positive, but there is usually more than 70% to 80% immunoglobulin A (IgA) bead binding with clinically significant sperm autoimmunity. Tail tip–only IBT binding is not significant.⁶⁵ The mixed antiglobulin reaction test is an alternative to the IBT.⁶⁰ The indirect IBT in which normal donor sperm are exposed to test serum or seminal plasma can be used to test men with too few motile sperm for the direct IBT. An alternative screening method for sperm autoimmunity in men with sperm in the semen would be to perform a sperm-mucus penetration test.⁶⁰

Sperm-mucus penetration tests can be performed by postcoital examination of sperm in cervical mucus collected at mid-cycle or after estrogen treatment (ethinyl estradiol, 50 g twice daily for 4 days) to produce mucus of equivalent quality.⁶⁰ In vitro capillary mucus penetration (Kremer) tests are particularly important for evaluating the significance of sperm autoantibodies; failure of sperm to penetrate more than 2 cm in 1 hour indicates severe sperm autoimmunity with a poor prognosis and a high likelihood of failed fertilization with standard IVF.^{35, 65}

Sperm Function Tests

A number of tests of sperm function are available to examine the human fertilization process (Fig. 3). These are only performed in specialist laboratories. If simpler approaches or active preparations of zona pellucida (ZP) or sperm receptor proteins become available, they will be widely used to improve the assessment of human sperm. IVF has permitted many conventional and new tests of sperm function to be examined. Groups of sperm variables that are independently significantly related to the proportion of oocytes that fertilize in vitro can be determined by regression analysis.⁶⁶ This approach has confirmed the importance of sperm morphology in the ability of sperm to interact with the coverings of the oocyte.

Human Sperm–Zona Pellucida Binding Ratio Test

Because the number of sperm bound to the ZP is strongly related to the fertilization rate, human sperm–ZP interaction tests have been developed using oocytes that failed to fertilize in vitro.⁶⁶ These oocytes can be used either fresh or after storage in concentrated salt solutions. Because the ZP binding capacity is variable, control (fertile donor) and test sperm are labeled with different fluorochromes (fluorescein and rhodamine). After incubation with equal numbers of control and test sperm, the oocytes are aspirated through a wide bore pipette to dislodge loosely adherent sperm and the numbers of sperm tightly bound to the ZP are counted with a fluorescence microscope. Results are expressed as a ratio of the number of test and control sperm bound to the ZP of four oocytes. An alternative method is to cut the zonae and expose one half to test and the other to control sperm (Hemizona assay).⁶⁷

Human Sperm–Zona Pellucida Penetration Test

It is difficult to determine the number of sperm penetrating the ZP when many sperm are bound to the surface. The sperm bound to the surface of the ZP can be sheared off by repeatedly aspirating the oocyte with a pipette with an internal diameter less than the diameter of the oocyte (120 m). The sperm penetrating the ZP or perivitelline space can then be counted easily, and the results of this test are the most predictive of fertilization rates with standard IVF.⁶⁶

Zona Pellucida–Induced Acrosome Reaction Test

Sperm dislodged from the ZP can be stained with a fluorescein-labeled lectin such as pisum sativum agglutinin or an antibody specific for the acrosomal contents to determine the proportion that are acrosome reacted. This test is useful for diagnosis of disordered ZP-induced acrosome reaction.⁶⁶

Human Sperm–Oolemma Binding Ratio Test

Sperm-oolemma binding has been studied in a similar way to the sperm-ZP binding test, using oocytes that have had the ZP removed. ⁶⁶

Interpretation of Semen Analysis Results

Table 5 shows various patterns of abnormality of semen quality and their common causes. It is always important to consider whether the result is spurious. Repeated tests are necessary to establish an average and to determine the variability within an individual man (see Fig. 2).

Variations in Semen Volume and Appearance

Low semen volume suggests incomplete collection, short duration of abstinence from ejaculation before the test, absence or obstruction of the seminal vesicles, or androgen deficiency. High semen volume (>8 mL) may be seen in association with oligospermia but is of little practical significance. Hemospermia is usually the result of minor bleeding from the urethra, but serious conditions, such as genital tract tumors, must be excluded. Other discoloration of the semen may indicate inflammation of accessory sex organs. The semen may be yellow with jaundice or salazopyrine administration. Defects of liquefaction and viscosity are relatively common and presumably result from malfunction of the accessory sex organs. Although these may cause problems with semen analysis and preparation of sperm for assisted reproductive technology (ART), they are probably of little relevance to fertility. Sperm agglutination is common with sperm autoimmunity but can also occur for other reasons.

Azoospermia

The total absence of sperm from the semen needs to be confirmed in repeated tests with vigorous centrifugation of the semen and careful examination of the pellet.⁶⁰ Rarely, an illness or difficulty with collection will cause transient azoospermia; however, this can also occur for unexplained reasons. With severe spermatogenic disorders and some obstructions, sperm may be present in the semen intermittently. If any live sperm can be found, these can be cryopreserved for intracytoplasmic sperm injection (ICSI).

Oligospermia

Sperm concentrations of less than 20 million/mL are classified as oligospermic.⁶⁰ This figure probably derives mainly from the work of MacLeod and Gold, who found that only 5% of fertile men had sperm concentrations less than 20 million/mL.⁶⁸ Recent studies of fertile men generally support 20 million/mL as a clinically useful figure although the new edition of the WHO semen analysis manual will suggest lowering the cutoff to 14 million/mL and also lower values for sperm motility and normal morphology.^{9, 69-71} There is a correlation between sperm concentration and other aspects of semen quality. Both motility and morphology are usually poor with oligospermia.

Asthenospermia

Asthenospermia is defined as less than 50% sperm motility or less than 25% with rapid progressive motility.⁶⁰ Spurious asthenospermia caused by exposure of sperm to rubber (particularly condoms), spermicides, extremes of temperature, or long delays between collection and examination, should be excluded. Low sperm motility is a frequent accompaniment of oligospermia, and is often also associated with a mixed picture of morphologic defects suggesting defective spermiogenesis.

Specific ultrastructural defects of the sperm can be evaluated by electron microscopy when there is zero sperm motility or extreme asthenospermia (less than 5% motile sperm).^{43, 72} Absent dynein arms, other axonemal defects, mitochondrial abnormalities, disorganized fibrous sheath or outer dense fibers, or normal ultrastructure may be found. Standard semen analyses usually show normal sperm concentrations and morphology but there may be tail abnormalities: short, straight, or thick tails, or midpiece defects. Viability tests help to distinguish this group of patients from those with necrospermia.⁷³ Patients with structural defects in the sperm may be able to be treated by ICSI. Asthenospermia may also be associated with sperm autoimmunity. The causes of other motility defects of moderate degree are unidentified.

Necrospermia

It is important to distinguish necrospermia from other types of severe asthenospermia because some patients produce pregnancies despite the low sperm motility.^{33, 73-75} Necrospermia is characterized by usually less than 20% to 30% total motility, less than 5% progressive motility, and a viability test less than 30% to 40%, indicating a high proportion of dead sperm. Other causes of severe asthenospermia such as sperm autoimmunity and collection problems must be excluded. Necrospermia may fluctuate in severity, particularly with changes in coital frequency.^{73, 75} Characteristic of necrospermia is an improvement of sperm motility with increased frequency of ejaculation. The condition may be caused by defective storage of sperm in the tails of the epididymides or stasis in the genital tract, and it also occurs with chronic spinal cord injury and with adult polycystic kidney disease associated with cysts in the region of the ejaculatory ducts.^{33, 74} There are ultrastructural features of degeneration in the ejaculated sperm but normal structure of late spermatids in testicular biopsies.^{73, 74} Treatment with antibiotics may have a beneficial effect, but this is not proved. The couple should have intercourse once or twice every day for 3 to 4 days up to the time of ovulation.

Teratospermia

Teratospermia is a reduced percentage of sperm with normal morphology assessed by light microscopy.⁶⁰ It is important to distinguish mixed abnormalities of sperm morphology from those in which all or the majority of sperm show a single uniform defect, such as spherical heads with absence of the acrosomes (globospermia) and pinhead sperm. Pinhead sperm result when the centrioles from which the sperm tails develop are not correctly aligned opposite the developing acrosome. On spermiation, the sperm heads are disconnected from the tails and absorbed during epididymal transit so that there are only sperm tails in the ejaculate, the cytoplasmic droplet on the midpiece giving the pinhead appearance.⁷⁶ Both these conditions cause sterility but are extremely rare.

In general, human spermatozoa are very variable in appearance and the microscopic assessment of sperm morphology is highly subjective and difficult to standardize between laboratories. Only a small proportion (<25%) of the motile sperm from fertile men are capable of binding the ZP in vitro, and this zona binding capacity is closely related to the morphology of the sperm head.⁷⁷ The morphometric characteristics of the sperm that bind to the ZP may be useful as a standard for sperm morphology.^{10, 78} Various histological assessments of morphology have been used. The simplest is to record as normal only those sperm that have no shape defects in head, midpiece or tail, regions.⁶⁰ In the strict morphology approach, although size measurements are set, the sperm are assessed by eye and those marginally abnormal are assigned abnormal. Automated methods involving image analysis by computer have been developed that could overcome the between-laboratory variability and greatly improve the predictive value of semen analysis for natural conception.^{10, 78}

Before the introduction of ICSI, the percentage of sperm with normal morphology assessed by strict criteria after washing the sperm and adjusting the concentration to 80 million/mL, provided one of the most useful predictors of fertilization rates with standard IVF. There was a progressive reduction in oocytes fertilized from 60% to 20% as abnormal morphology increased from less than 70% to more than 95%.⁷⁹ Patients with high proportions of sperm with abnormal morphology are now treated by ICSI because of the risk of failure of fertilization with standard IVF. ICSI results are independent of sperm morphology.