Male Infertility Overview

Several somatic chromosomal abnormalities are associated with male infertility. In a study of 1,263 barren couples, it was found that the overall incidence of male chromosome abnormalities was 6.2%. In a subgroup in which the male partner's sperm count was less than 10 million, the incidence rose to 11%. In azoospermic subjects, 21% had significant chromosomal abnormalities. Only in isolated cases however, has infertility been documented in association with a specific chromosomal abnormality i.e. D-D translocations, ring abnormalities, reciprocal translocation, and various other aberrations. Chromosomal studies though should be considered in men with severe oligospermia or azoospermia to look for autosomal and sex chromosomal abnormalities.

Klinefelter's Syndrome is a genetic disorder due to the presence of an extra X chromosome in the male, the common karyotype being either 47,XXY which is the classic form or 46,XY/47,XXY the mosaic form. The incidence is about 1:500 males. Characteristically, these individuals have small, firm testes, delayed sexual maturation, azoospermia and gynecomastia. Because the features of hypogonadism are not evident until puberty, the diagnosis is delayed. The decrease in testicular mass is usually due to sclerosis and hyalinization of the seminiferous tubules. The testes characteristically have a length of less than 2 cm and 12 cc volume. LH and FSH levels are characteristically elevated. Testosterone levels can range from normal to low and decrease with age. Serum estradiol levels are often increased. The higher estrogen levels relative to testosterone cause the feminized appearance in gynecomastia. About 10% of these patients have chromosomal mosaicism. The mosaics have less severe features of Klinefelter's Syndrome and may be fertile, as there may be a normal clone of the cells within the testes. Mild mental deficiency and restrictive pulmonary disease occur more frequently in these patients than in the general population. The infertility is reversible and later in life most of these men will require androgen replacement therapy for optimal virilization and normal sexual function.

XX Disorder or Sex Reversal Syndrome is a variant of Klinefelter's Syndrome. The signs are similar except for the average height is less than normal, hypospadias is common and a decreased incidence of mental deficiency. These patients have a 46,XX chromosome complement. This paradox is explained by the fact that their cells express H-Y antigen and are presumed to have a Y chromosome somewhere in their genomes. The incidence of the XYY syndrome is the same as that of Klinefelter's Syndrome but its phenotypic expression is more variable. Semen from these subjects may vary from azoospermic to normal. These patients are excessively tall and have had pustule acne. A percentage have anti-social behavior. Most have a normal LH and testosterone level with the FSH level dependent on the extent of germ cell damage. There is no treatment for their infertility.

Noonan's Syndrome is the male counterpart of Turner's Syndrome (X0), and these individuals typically have similar features i.e. short stature, web neck, low-head ears, cubitus valgus, ocular abnormalities and cardiovascular abnormalities. Most males with Noonan's Syndrome have cryptorchidism and diminished spermatogenesis and are infertile. Those with diminished testicular function will have elevated serum FSH and LH levels. They demonstrate on chromosomal analysis a sex chromosome abnormality such as X0/XY mosaicism. There is no treatment for their infertility.

Patients with myotonic dystrophy suffer from delayed muscle relaxation after initial contraction. The major clinical features also include lenticular opacities, frontal baldness and testicular atrophy. Inheritance is autosomal dominant and the expression is variable though 80% will develop testicular atrophy. Pubertal development is usually normal and testicular damage occurs later in adult life. Leydig cell function remains normal and there is no gynecomastia.

Bilateral anorchia or vanishing testes syndrome is an extremely rare disorder effecting about 1 in 20,000 males. Patients will present at birth with non-palpable testes and sexual immaturity later in life because of the absence of testicular androgens. The karyotype is normal, but LH and FSH levels are elevated and testosterone is extremely low. In utero the testes may have been lost due to torsion, trauma, vascular injury or infection. However, functioning testicular tissue must have been present at least for the first trimester of fetal life in order for the male reproductive ducts and for the external genitalia to differentiate along male lines. Testosterone does not increase in response to HCG stimulation. These patients have eunuchoid proportions but no gynecomastia. Therapy can only be directed at the testosterone deficiency.

Sertoli-cell-only syndrome or germinal cell aphasia may have several causes including congenital absence of the germ cells, genetic defects, or androgen resistance. Upon testicular biopsy there will be complete absence of germinal elements. Clinical findings include azoospermia in association with normal virilization, testes of normal consistency but slightly smaller in size, and no gynecomastia. Testosterone and LH levels are normal but FSH levels are usually elevated. Sometimes in patients who have had other testicular disorders like mumps, cryptorchidism or radiation/toxin damage, the seminiferous tubules may also contain only Sertoli cells, but in these men the testes are small and the histologic pattern is not as uniform. These patients are more likely to have severe sclerosis and hyalinization as prominent features as well. There is no treatment for their infertility.

Gonadotoxins like drugs and radiation can effect the germinal epithelium because it is a rapidly dividing tissue and susceptible to interference of cell division. Cancer chemotherapy has a dose-dependent effect on testicular germinal epithelium. The germinal epithelium appears to be more resistant to toxic drugs before puberty than in adulthood. The alkylating agents like chiromancies, cyclophosphamide and nitrogen mustard are particular toxic to the testes. In some patients, cryopreservation of semen can be performed before cancer chemotherapy is begun. Cyproterone, ketoconazole, spirolactone and alcohol all interfere with testosterone synthesis. Cimetidine is a testosterone antagonist, blocking peripheral testosterone action. These men will often present with gynecomastia and have decreased sperm counts.

Recreational drugs like marijuana, heroin, and methadone are associated with lower serum testosterone levels without a concomitant elevation in LH levels. This suggests a central abnormality as well as a testicular defect. Certain pesticides like dibromochloropropane have been found to impair testicular function in men. Germ cells are particularly sensitive to radiation while the Leydig cells are relatively resistant. At exposures below 600 rads, germ cell damage is reversible. Above this level of exposure though permanent damage is likely. Recovered spermatogenesis may take up to 2-3 years even in men who receive low doses of radiation. Elevated FSH levels reflect the impaired spermatogenesis, with return to normal once the testes recover.

About 15-25% of adult men who contract mumps can develop orchitis which is more commonly unilateral though bilateral involvement occurs in about 10% of affected men. Testicular atrophy can develop within 1 to 6 months or may take years. Fewer than one-third of men with bilateral orchitis recover normal semen parameters.

The exposed position of the testicles make them susceptible to trauma and subsequent atrophy. Iatrogenic injury may occur during inguinal surgery and interfere with testicular blood supply or damage the vas deferens.

Systemic diseases like renal failure resulting in uremia in males is associated with decreased libido, impotence and altered spermatogenesis and gynecomastia. LH and FSH levels are elevated and testosterone levels are decreased. The cause of hypogonadism in uremia is probably multifactorial. It has been found that serum prolactin levels are elevated in one-fourth of the patients. An excess in estrogen may be contributory. Anti-hypertensive drugs and uremic neuropathy may also play a role in uremic impotence and hypogonadism. After successful renal transplantation, uremic hypogonadism improves. A large percentage of males with cirrhosis of the liver have testicular atrophy, impotence and gynecomastia. Testosterone levels are decreased. Estradiol is increased as a result of decreased hepatic extraction of androgens with increased conversion to estrogen peripherally. LH and FSH levels are only moderately elevated relative to the low serum testosterone levels. Ethanol also acutely reduces testosterone levels by inhibiting testicular testosterone synthesis. Many men with sickle cell disease have evidence of hypogonadism. Even though LH and FSH levels may be variable, testosterone levels are low. Hypogonadism of sickle cell disease is likely secondary to a mixture of testicular and pituitary-hypothalamic causes.

Rare heredity disorders due to enzymatic defects can result in defective testosterone synthesis and are associated with an adequate virilization that is evident at birth as ambiguous genitalia. Several forms of androgen resistance result in under masculinization and infertility in males with otherwise normally developed external genitalia. Diagnosis is made by the finding of abnormal androgen receptors in a culture of genital skin fiberblasts. Characteristically, there is an elevation testosterone and LH levels. Proof of this is costly and there is no treatment for their infertility.

Cryptorchidism is a common developmental defect incidence of 0.8% in adult males. The undescended testes become morphologically abnormal after age 2. Though in spite of prophylactic orchidopexy, unilateral cryptorchid patients have reduced fertility potential. It appears that in the cryptorchid individual, there is dysgenesis of both the normally and abnormally descended testis. Semen quality is particularly poor in patients with bilateral undescended testicles. Even though baseline serum FSH, LH and testosterone levels may be normal, there is a super normal response of both LH and FSH to generate stimulation which reflects compromised testicular function.

A scrotal varicocele is the most common causative finding in infertile men. It results from backflow of blood secondary to incompetent or absent valves in the spermatic veins. This valvular deficiency combined with the long vertical course of the internal spermatic vein on the left side, leads to the formation of most varicoceles on the left side (90%). Varicoceles are not as commonly seen on the right side because of the oblique course of the right internal spermatic vein from the vena cava. A unilateral right-sided varicocele suggests venous thrombosis/tumor or situs inversus. Newer diagnostic tests have shown the incidence of bilateral varicoceles to be greater than 40%. The incidence of varicoceles in the adult male population is approximately 20% and in the infertile population approximately 40%. 50% of men with varicoceles will have impaired semen quality, but many men varicoceles are fertile. To explain the abnormalities in spermatogenesis with varicocele, the following theories have been proposed:

Recent experimental evidence has demonstrated bilateral increase in both testicular blood flow and temperature with altered spermatogenesis. Unfortunately, at least 25-40% of infertile men have idiopathic infertility for which no cause can be identified. More known causes will be discovered hopefully as knowledge of male reproductive physiology expands.

Congenital disorders of sperm transport are rarely due to absence or atresia of portions of the male ductal system. Males with cystic fibrosis have a high incidence of congenital hypoplasia or absence of the major portion of the epididymis, vas deferens, and seminal vesicles. Absence of the seminal vesicles is always associated with azoospermia, semen that does not coagulate at ejaculation, and absence of fructose. In Young's Syndrome which is associated with pulmonary disease, the ultrastructure of the cilia is normal but the epididymis is obstructed due to inspissated material leaving these patients azoospermic.

Acquired disorders of sperm transport are usually due to bacterial infections which may acutely or chronically involve the epididymis with subsequent scarring and obstruction. Apart from vasectomy, the vas may accidentally be ligated during hernia repair, orchiopexy, and even during varicocelectomy.

Functional obstruction of sperm transport results from neuropathic insults like injuries to the sympathetic nerves during retroperitoneal lymph node dissection or pelvic surgery. This may cause lack of peristalsis of the vas deferens with resultant lack of emission and/or failure of the bladder neck to close at the time of ejaculation leading to retrograde ejaculation. Diabetic males with autonomic neuropathy frequently present with both erectile dysfunction and/or retrograde ejaculation. Spinal cord injury can result in paraplegia or quadriplegic with resultant erectile dysfunction and lack of emission and ejaculation. There are many medications such as tranquilizers, antidepressants, and antihypertensives that may interfere with the sympathetic nervous system as well.

Disorders of sperm motility and function exist secondary to problems that include congenital defects of the sperm tail, maturation defects and immunologic defects. Immotile cilia syndrome is a group of disorders characterized by immotility or poor motility of spermatozoa tie. Kartagenerss Syndrome). In these disorders, testicular biopsy is normal and the sperm count adequate but sperm motility is either markedly reduced or absent. The defective structural abnormality leading to impairment of both the cilia and spermatozoa is seen only with the electron microscope. The defects known to cause immotile cilia syndrome include absent dynein arms, short or absent spokes with no central sheath and missing central microtubules. Motility problems may also be associated with a deficiency of the protein carboxylmethylase in the tail of the sperm. Normal sperm counts with poor motility following vasectomy reversal may be a result of epididymal dysfunction. Chronic intratubular pressure following vasectomy may have a deleterious effect on the epididymis such that spermatozoa may not gain their usual maturation and capacity for motility. Breakdown of the blood-testes barrier by infection, trauma or operation allows sensitization of the spermatozoa antigens. Sperm antibodies may be a relative cause of infertility in about 3-7% of infertile males. Immunity does not appear to be an all-or-none phenomenon but may contribute to reduced fertility potential.

Infections. High concentrations of gram-negative bacteria like E-coli in the semen can impair sperm motility. Sexually transmitted organisms such as chlamydia trichomatous, mycoplasma hominis and ureaplasma urealyticulum have rarely been implicated in reproductive failure. In both animals and humans, there is no convincing evidence to support the use of routine cultures or empiric therapy in asymptomatic infertile males.

Sexual dysfunction has been reported in up to 20% of infertile males. Decreased sexual drive, erectile dysfunction, premature ejaculation and failure of intromission are all potentially correctable causes of reproductive failure. Decreasing libido and erectile dysfunction may reflect low serum testosterone levels with an organic cause. Performance anxiety is also often reported and often abated with reassurance.

Semen Analysis
Although semen analysis is not a test of fertility, a carefully performed semen analysis is a highly predictive indicator of the functional status of the male reproductive hormonal cycle, spermatogenesis and the patency of the reproductive tract. The initiation of a pregnancy is the only true measure of fertility and is a couple-related phenomenon. One must keep in mind that normal values have been difficult to determine for fertile men in their reproductive years. Clinical studies of infertile patients have established "limits of adequacy" below which the chance of initiating a pregnancy becomes more difficult. These parameters are not absolute because some fertile men may have values below these "limits of adequacy". Conversely, infertile men may have normal semen parameters by standard analysis techniques because standard evaluation does not assess the functional integrity of the sperm. The World Health Organization Laboratory Manual for Examination of Human Semen and Semen-Cervical Mucous Interactions is highly recommended for technical details.

Most specialists collect at least three specimens in which the seminal parameters are within 20% of each other before establishing a baseline for semen quality. The semen specimen is best obtained by masturbation after a two to three day period of abstinence. The specimen should be assessed within 1-2 hours of collection. Samples obtained by coitus interruptus or from silastic condoms devoid of spermatocidal agents are less desirable but satisfactory. Therefore, collection at the site of analysis is ideal. Besides laboratory error, there are variations in sperm density, motility and morphology among multiple samples from a given man. Abstinence intervals give s large source of variability. With each day of abstinence (up to one week) semen volume increases by 0.4 cc, sperm concentration by 10-15 million per cc, and total sperm count by 50-90 million. Sperm motility and morphology appear to be unaffected by 5-7 days of abstinence, but longer periods lead to impaired motility. Interpretation of semen analysis must take into consideration the variations between samples that exist in individuals. The minimum number of specimens to define good or poor quality of semen is three samples over a 6-8 week interval with a consistent period of abstinence of 2-3 days. In a longitudinal analysis of semen from both fertile and infertile men, it was found that 97% of men with initial good sperm concentration would continue to show good density after as many as 3-6 specimens. Those rated poor at first also remained poor in future visits. For those rated equivocal, first visit was of little value and at least three visits were needed to obtain stability.

Semen volume must be taken into consideration assessing total sperm production by the testes. Semen volume per se, however, effects fertility only when it falls below 1.5 cc due to the inadequate buffering of vaginal acidity or when the volume is greater than 5 cc. Low volumes may be associated with incomplete collection, retrograde ejaculation, ejaculatory duct obstruction, or androgen deficiency. For most clinicians, a sperm concentration of less than 20 million per cc is the lower limit of normal. Sperm motility is the single most important measure of semen quality and can be a compensatory factor in men with low sperm counts.

Sperm motility is usually rated in two ways: the number of motile sperm as a percentage of the total, and the quality of forward progressive sperm movement i.e., how fast and how straight the sperm swims. The degree of forward progression is a classification based on the pattern displayed by the majority of motile sperm. It ranges from zero (no movement) to 4 (excellent forward progression). Typically, you want to see at least 50% of the sperm with good forward progression. Microscopic evaluation of the liquefied semen may reveal agglutination (clumping) of sperm. Agglutination may be head-to-head, head-to-tail, or tail-to-tail and may suggest an inflammatory or immunologic process. Sperm morphology is subject to great variation and it is unusual to see specimens that contain more than 80% normal sperm heads.

Morphology is assessed on stained seminal smears and is scored; after viewing at least 100 cells. Typically, you like to see at least 30% of the sperm having normal oval heads, mid piece and tail. No longer is it felt that increased numbers of tapered, amorphous and immature cells (stress pattern) are pathonomic of varicoceles, but rather represent altered testicular function. Semen from normal men coagulates and then over 20-30 plus minutes liquefies. Delayed liquefaction of semen greater than 60 minutes may indicate disorders of accessory gland function. Diagnosis of the liquefaction problem should be made if there is absence of sperm in the post coital test. If sperm are capable of reaching the cervical mucus, problems of semen liquefaction are not clinically relevant. Increased semen viscosity, which is unrelated to the coagulation-liquefaction phenomenon, signifies a disorder of accessory gland function and may effect the accuracy of assessment of both sperm density and motility. It is only clinically relevant when there are very few sperm in the post coital test.

The presence of white blood cells in semen should be noted. It is difficult to differentiate between white blood cells and immature spermatozoa on routine analysis, because both may appear as round cells in the semen. Peroxidase stain and, more recently monoclonal antibodies have been utilized to aid in this differentiation. Excessive white cells ( > 1 million/cc) may indicate an infection that may contribute to subfertility. If no spermatozoa are observed, a qualitative test for fructose should be performed. A low ejaculate volume and lack of fructose, along with failure of the semen to coagulate, suggest congenital absence of the vas deferens and seminal vesicles or obstruction of the ejaculatory ducts. Fructose is androgen-dependent and is produced in the seminal vesicles.

Computer-assisted semen analysis (CASA) systems couple video technology and sophisticated microcomputers for automatic image digitalization and processing. This technology was developed for more objective measurements of seminal parameters over the subjective measures of standard semen analysis. CASA permits the measurement of additional motility parameters such as curvalinear velocity, straight-line velocity, linearity, and flagellar beat frequency. Under certain circumstances, CASA has been found to be less accurate than the standard semen analysis and the biological and clinical relevance of some of these new parameters has yet to be validated.

Most cases of male infertility are non-endocrine in origin. Routine evaluation of hormonal parameters is not warranted unless sperm density is extremely low or there is clinical suspicion of an endocrinopathy. The incidence of primary endocrine defects in infertile men is less than 3%. Such defects are rare in men with a sperm concentration of greater than 5 million per cc. When an endocrinopathy is discovered, however, specific hormonal therapy is often successful. Because of the episodic nature of LH secretion and its short half life, a single LH determination has an accuracy of plus or minus 50%. Similarly, testosterone is secreted episodically in response to LH pulses and has a diurnal pattern with an early morning peak. Serum FSH has a longer half life, and these fluctuations are less obvious. Therefore, I usually just check an FSH and testosterone level. A low testosterone level is one of the best indicators of hypogonadism of hypothalamic or pituitary origin. Low LH and FSH values concurrent with low testosterone levels indicate hypogonadotropic hypogonadism. Elevated FSH and LH values help to distinguish primary testicular failure (hypergonadotropic hypogonadism) from secondary testicular failure (hypogonadotropic hypogonadism). Most patients with primary hypogonadism have severe, irreversible testicular defects. On the other hand, secondary hypogonadism has a hypothalamic or pituitary origin and infertility may be correctable. Elevated FSH levels are usually a reliable indicator of germinal epithelial damage and are usually associated with azoospermia or severe oligospermia, depicting significant and usually irreversible germ cell damage. In azoospermic and severely oligospermic patients with normal FSH levels, primary spermatogenic defects cannot be distinguished from obstructive lesions by hormonal investigation alone. Therefore, scrotal exploration and testicular biopsy should be considered. An elevated FSH level associated with small, atrophic testes implies irreversible infertility and a biopsy is not warranted.

The diagnostic value of prolactin measurement is extremely low in men with semen abnormalities unless these are associated with decreased libido, erectile dysfunction, and evidence of hypogonadism. Prolactin measurement is warranted in patients with low serum testosterone levels without an associated increase in serum LH levels.

Individuals with gynecomastia, obesity, history of alcohol abuse, or suspected androgen resistance should have a serum estradiol level. In men with a history of precocious puberty, one should consider congenital adrenal hyperplasia. In the common variant (21-hydroxylase deficiency), serum levels of 17-hydroxyprogesterone are elevated. In 11-hydroxylase deficiency, serum 11-Deoxycortisol levels are elevated.

In patients with hypogonadotropic hypogonadism, the pituitary hormones other than LH and FSH should also be assessed like adrenal corticotropic hormone (ACTH), thyroid stimulating hormone (TSH), and growth hormone (GH). Thyroid dysfunction is such a rare cause of infertility that routine screening for thyroid abnormality should be discouraged.

Only in isolated cases has infertility been documented in association with a specific chromosomal abnormality. Subtle genetic studies can be considered in men with severe oligospermia and azoospermia to look for both autosomal and sex chromosomal abnormalities. The diagnostic yield is greatest in men with small testes, azoospermia, and elevated FSH levels.

Antisperm antibodies, although not an absolute cause of infertility, appear to be capable of reducing the likelihood of pregnancy. The concentration of antisperm antibodies in the semen influence the degree of impairment. Antisperm antibodies do not lyse or immobilize sperm. They have not generally been found to be associated with decreased density or motility, but they do appear to interfere with sperm function by simply attaching to the plasma membrane of the spermatozoa. Sperm agglutination may be caused by antisperm antibody attachment. Infections may lead to agglutination of sperm as well though. Whenever agglutination is observed, the possibility of infection should be evaluated with appropriate semen cultures. Antisperm antibodies should be suspected in couples with repeated abnormal post coital tests. Antisperm antibodies appear to interfere with normal penetration and transit of sperm through normal cervical mucus.

Antisperm antibodies also should be suspected in subfertile men with a history compatible with disruption of the integrity of the genital tract, and when sperm agglutination or reduced motility is observed on semen analysis. Immunological factors may also play a role in the pathogenesis of 10-20% cases of "unexplained infertility". Antisperm antibodies can be found either in the circulation or in the seminal plasma or directly on the sperm surface. Studies have shown a discordance between the results of sperm antibody tests in matching serum and sperm samples. The presence of humoral antibodies directed against sperm is not relevant to fertility unless these circulating antibodies are also present within the reproductive tract. Therefore, the convenience of assaying blood for antisperm antibodies is outweighed by the lack of clinical relevance of these measurements in comparison with assays that identify the immunoglobulins directly on the sperm surface. It appears therefore that tests capable of detecting antisperm antibodies on living sperm are the most direct way to determine whether a significant autoimmunity to sperm exists. The immunobead binding test (IBT) is one of the most informative and specific of all assays currently available to detect antisperm antibodies bound to the surface of sperm.

Sperm-Cervical Mucus Interaction
For fertilization to take place in-vivo, the sperm must be able to get past the cervical mucus. The post coital test assesses the ability of sperm to penetrate and progress through cervical mucus. Cervical mucus is examined 2-8 hours after intercourse at the time of expected ovulation. The presence of greater than 10-20 motile sperm per high power field is generally accepted as a normal post coital test. Post coital testing is a bio-assay that provides information concerning sexual function, motility of the sperm, and the sperm-mucus interaction. A positive result implies normal semen and mucus. A poor result in an individual with normal semen parameters implies either cervical abnormality or the presence of sperm antibodies. Sperm-mucus interaction may also be assessed in-vitro. This allows for some degree of standardization. Human or bovine ovulatory mucus is placed in a capillary tube. Sperm penetration into the mucus is measured over a fixed period of time. These in-vitro techniques enable one to compare patient specimens with fertile sperm and control some of the variables associated with standard post coital testing.

Sperm Penetration Assays
Penetration of an oocyte requires sperm capacitation, acrosome reaction, fusion and incorporation into the oocyte. Cross-species fertilization is normally prevented by the zona pellucida. Hamster eggs stripped of the zona pellucida can be penetrated by human sperm. This in-vitro functional test measures the penetration ability of the sperm. The end point of this assay is penetration of the ovum and decondensation of sperm heads. The percentage of oocytes penetrated and the number of sperm penetrating each oocyte are measured. Sperm that are capable of multiple penetrations per oocyte appear to have greater fertilizing potential than sperm that do not penetrate. The results of the sperm penetration assay (SPA) have primarily been used to predict the results of assisted reproductive techniques, in particular, in-vitro fertilization. Men with sperm of low SPA score are less likely to achieve a spontaneous pregnancy than those with a high SPA score. It must be emphasized that the abnormal penetration does not indicate that fertilization cannot occur, nor does good penetration assure fertilization. Although variations still exist between laboratories, there appears to be general agreement that less than 10% penetration is evidence of sperm dysfunction and male infertility. Indications for SPA include unexplained infertility, and its use is also recommended prior to expensive assisted reproductive techniques. Although the SPA is a reliable indicator of the fertilizing capacity of human spermatozoa, it does not predict the ability of sperm to bind to and penetrate zona pellucida or the sperm's motility and progression in the female reproductive tract.

For as SPA with zona free hamster eggs can demonstrate completion of the human sperm acrosome reaction and sperm oocyte plasma membrane fusion, only tests with human zona pellucida can assess the capability of human sperm to bind to the human oocyte. The hemizona assay uses zona pellucida from non-living human oocytes that have been microsurgically bisected. Sperm are allowed to interact and bind with the hemizona. The patient's sperm and fertile sperm are compared utilizing the identical halves of hemizona. The results are expressed as the hemizona index, i.e. bound sperm by the subfertile man divided by bound sperm from the fertile donor multiplied by 100. This assay requires significant expertise in micromanipulation. The hemizona assay is not indicated in the routine evaluation of the subfertile man.

Acrosome Evaluation
The acrosome reaction is necessary for fertilization to take place. Evaluating the ability of sperm to undergo the acrosome reaction may provide an additional assessment of sperm function. It is possible to determine the acrosomal status of sperm by utilizing electron microscopy, staining, immunofluorescent techniques and monoclonal antibodies. It is also possible to induce an acrosome reaction with ionophores and human zona pellucida. These techniques are labor-intensive and the ability of the acrosomal status to predict fertility must be confirmed.

Hypo-osmotic Swelling
It has been found that when sperm from normal fertile men are exposed to a known solution of fructose and sodium citrate, 33-80% of the spermatozoa will exhibit tail swelling. Sperm that are not viable or sperm with non-functioning membranes do not swell. This appears to be explained by the ability of the normal cell membrane to maintain an osmotic gradient. Attempts have been made to correlate this finding with the fertilization potential for semen samples. Samples with greater than 62% swelling are able to fertilize ova, whereas less than 60% swelling is observed in samples of infertile semen. This test has not been widely embraced and is currently a research tool.

If urinalysis is abnormal or bacterial prostatitis is implicated by either the history or physical examination, appropriate cultures are indicated. The common sexually transmitted organisms such as chlamydia trachomatis, mycoplasma hominus and ureaplasma urealyticulum have been implicated in reproductive failure in animals and humans. On the basis of this supposition, physicians have instituted antibiotic therapy without obtaining evidence of infection in the hope of improving fertility. We currently could find no evidence for the role of current asymptomatic infection due to the above organisms in male infertility. Without evidence of inflammation, there is no indication for routine culture or antibiotic treatment of infertile men.

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