An In-Depth Look at Male Infertility

Reprinted with Permission by DrRajMD

In the medical study and practice of human reproduction, infertility is usually defined as the inability to conceive (become pregnant) after 1 year of trying. The term infertility is not the same as sterility, since many couples ultimately may achieve a pregnancy after 1 year of unprotected intercourse.

Over 4.5 million American men and women - or roughly 1 out of 5 (15-20%) couples - fail when attempting their first pregnancy. In these couples, about half of the men will have a significant abnormality that makes them unable to father children. Male infertility may be caused by abnormalities in the testes or other areas of the male reproductive tract, as well as immune system defects. Yet the most common cause of male infertility is disordered sperm production. Fortunately, new diagnostic tests are available to help define some of the more obscure causes of male infertility. Specialists should perform an initial screening of the male partner whenever a couple complains of infertility.

Evaluation

Infertility is currently a problem for 1 out of every 5 couples trying to have children. If, after a year of trying to conceive, a couple is still unsuccessful, a basic infertility evaluation may be initiated. If, however, the female partner is over thirty years old or has a significant medical history of irregular menstrual cycles or recurrent pelvic infections, the infertility evaluation can be started earlier.

Any couple embarking on an infertility evaluation does so with some fear and reluctance. Some common concerns include: What is involved? Is it painful? Will it cause physical damage? How expensive is it? What will the doctor find? Then what? The whole world of doctor's offices, x-ray departments and hospitals is scary and stressful for many people. It often helps to know what is ahead, to be informed and aware of how it will feel and what the doctor is hoping to find.

The infertility evaluation or work-up itself follows a fairly predictable and specific sequence of tests and examinations. A complete reproductive evaluation of the woman usually takes 3 to 4 menstrual cycles to complete. This is because certain tests must be done at specific times during the menstrual cycle. The cost for a complete work-up can be as high as $3000.00 if laparoscopy is indicated. Insurance coverage varies. Some insurance companies do cover all the various tests required, while others do not.

The nature of the infertility evaluation necessitates that it become a priority in your daily life. Suddenly, there are specific days that you must have intercourse. For some tests, you will even have to report to the doctor's office a specific number of hours after intercourse for testing. As a result, spontaneous lovemaking becomes difficult. Vacations and business trips become a low priority. Schedules are altered to accommodate the demands of the testing cycles. Many women find it hard to take off from work, especially if they don't want it known that they are undergoing an infertility evaluation. Obviously, it can be a very stressful time. Both man and woman are being tested and "scored". There can be a feeling of "pass or fail" and a real sense of despair when a test comes back showing a negative or even questionable result. Women often feel frightened and violated by some of the more invasive fertility tests. Men often feel helpless. For the man, testing is over if the semen analysis is normal. In contrast, he may see his partner having to go through various tests that can be painful and scary. This can understandably upset both partners. Added to this uncertainty is the pervasive fear of what the doctors may find. What if they do find a cause, but it is a discouraging one? Needless to say, the decision to initiate a fertility evaluation is not a simple or easy one.

Most infertility specialists like to see the couple together for the first appointment. This provides an opportunity for the couple to establish good communication with their doctor. It is also an opportunity to evaluate what, if anything, has already been tried and what might be needed for future success. The doctor will be able to explain the tests to the couple and answer questions at this time. A schedule will also be provided, outlining the time frame during which she/he hopes to complete the evaluation work-up.

Medical History

To help diagnose the cause of a man's infertility, the physician will take a very careful medical history from the male. Attention will be paid to details concerning previous surgeries, infections, chronic illnesses or hospitalizations. Background information on smoking, recreational drug and alcohol use, medications and exposure to environmental or occupational toxins will be requested. Questions will be asked about specific childhood illnesses and development - such as mumps orchitis (inflammation of the testes), testicular trauma (injury) or torsion (twisting), undescended testes and/or orchiopexy (fixation of undescended testes in the scrotum), and onset of puberty. The physician will ask about recent medical history and infections - has the patient had any pelvic injuries, bodily illnesses, high-fever or viral infections, venereal diseases or tuberculosis? The physician also will want to know about the patient's family history - do any relatives have cystic fibrosis, androgen receptor deficiency, diabetes, etc. (see Causes of Male Infertility). Any history of previous pregnancies will be discussed. The history taking interview will be followed by a complete physical examination.

Additional clues to the diagnosis of male infertility will include factors such as prior operations - especially surgical procedures in the pelvic, inguinal (groin), scrotal or abdominal regions.

· Y-V plasty (repair) of the bladder neck in childhood. Y-V plasty involves removal of the internal sphincter muscle. It may result in retrograde ejaculation (backward release of semen into the bladder; see also Retrograde Ejaculation). Retrograde ejaculation is associated with acidic semen of low volume (less than 1 ml) and low sperm count (oligospermia) or lack of sperm in the semen (azoospermia). In affected patients, large numbers of sperm often are found in the urine following ejaculation.

· Surgery in the retroperitoneal (back of the abdominal lining) area. For example, cancer patients who have undergone removal of the lymph nodes from the retroperitoneal area (RPLND) may experience aspermia (failure to form sperm), lack of sperm emission, or retrograde ejaculation (see also Neurogenic Causes and Electroejaculation).

· Herniorrhaphy (hernia surgery), especially pediatric herniorrhaphy, which may result in injury to the genitals or urinary tract.

· Prostate resection (cutting away of all or a portion of the prostate gland).

Reproductive History

The physician will also review reproductive history. Was sexual maturation early or late? Did the patient ever have a sexually transmitted disease? What is the frequency and timing of intercourse? Does the patient use lubricants? Has the patient ever experienced any erection or ejaculation problems?

· Early puberty may suggest problems with the endocrine (hormonal) system, such as congenital adrenal hyperplasia (CAH) an overgrowth of adrenal gland tissue that may lead to decreased fertility.

· Late puberty may suggest Kallmann's syndrome, which is characterized by decreased function of the testes due to the absence of gonadotrophic hormone (see also Kallmann's syndrome).

· Prior sexually transmitted diseases (STDs) may have caused scarring, narrowing or blockage of genitourinary canals such as the epididymis (an elongated, coiled duct that provides for the maturation, storage, and passage of sperm from each testis), the vas deferens (the excretory duct of each testis), or the urethra (the tube that passes urine or semen out of the body).

· Sexual habits. Infertility problems often are due to a lack of understanding about the timing of intercourse. The best time to achieve pregnancy for the female partner is midway through the menstrual cycle. At this time, the most effective frequency of intercourse is every 24-48 hours, and the 6 days leading up to and including the day of ovulation (mid-cycle) are the most likely days for intercourse to lead to pregnancy. It is essential to have the presence of live sperm during the 12- to 24-hour period in which the egg is available to be fertilized.

· Use of lubricants. Lubricants should be avoided, as many are toxic to sperm or may impede sperm movement.

· Masturbation. Frequent male masturbation during the female partner's fertile ovulation time should be avoided, as it may deplete the sperm reserve.

· Potency. The inability to achieve or maintain an erection, premature ejaculation, or difficult ejaculation may suggest underlying physical problems that, while potentially correctable, may impede male fertility.

Other Factors

The physician also will seek information about exposure to harmful environmental and occupational toxins, chemicals, drugs (for example, chemotherapeutic medications and steroids), excessive heat, or radiation. If possible, the physician should be given:

· A list of all the medications currently taken (including nonprescription products) or that have been taken in the past.

· The dates of any exposures to environmental toxins, occupational toxins, chemicals, drugs, heat, or radiation and/or the results of tests for these.

Likewise, the physician will ask about physical symptoms or complaints. Particularly important symptoms or complaints may include:

· Respiratory infections or generalized illness. Fever or virus in the blood (viremia) can cause impaired testicular function that can affect sperm development for 1 to 3 months after the virus symptoms have cleared. Repeated respiratory tract infections or bronchiectasis may also be clues to the presence of immotile-cilia syndrome - in which the sperm tails are defective and cannot move - or Young's syndrome - in which material in the epididymis (coiled sperm duct) blocks the passage of sperm into the semen.

· Lack of a sense of smell (anosmia). Anosmia may be associated with over-secretion of the pituitary hormone prolactin (as caused by prolactin-secreting tumors such as micro- or macroadenomas), or with Kallmann's syndrome (see also Kallmann's syndrome and hyperprolactinemia).

· Impaired visual fields and galactorrhea (spontaneous milk production by the breasts) may be symptomatic of a prolactin-secreting tumor.

History of Infertility

Finally, the physician will inquire about the history of infertility: How long has the patient been unable to achieve pregnancy? Did the patient ever achieve prior pregnancies with a current and/or previous partner? Has the patient been evaluated for infertility or received previous treatments for infertility?)

Physical Examination

A physical exam is usually done on the first visit to the doctor's office. The purpose is to identify any signs or medical conditions that could cause infertility, such as a varicocele (enlarged "varicose" vein in the scrotum), abnormalities of the testes, penis, prostate or secondary sex traits.

Varicocele may be suggested by a difference in size between the left and right testes. However, since varicocele also may be difficult to detect, the physician will carefully feel the scrotum while the patient is lying down, standing up, and performing the Valsalva maneuver - bearing down on the pelvic floor muscles while holding the breath - as if to defecate.

Abnormalities of the testes - such as absence of the vas deferens or seminiferous vesicles - may be detected by thorough palpation (feeling) of the scrotum. The testes often are small and firm if the seminiferous tubules were injured before puberty. By contrast, if the seminiferous tubules were injured after puberty, the testes are likely to be small and soft. In most normal adult men, the testes are approximately 4.5 cm (1.75 in) long and 2.5 cm (1.0 in) wide, and they have an average volume of 20 cc (0.7 oz).

Next, the physician will look for indications of hypogonadism (delayed sexual maturity), as shown by immature secondary sex characteristics, including:

· abnormal male hair distribution (thin hair on the face, pubic area, underarms, and body; lack of hair recession at the temples);

· atypical, "eunuchoid" (eunuch-like; without testes) skeletal proportions (arm span 2+ in > height; upper body/lower body ratio infantile genitalia (small penis, testes, and prostate; underdeveloped scrotum); and

· underdeveloped muscle growth and low muscle mass.

Men with hypogonadism may experience other related disorders, such as color blindness, anosmia (lack of sense of smell), cleft lip (harelip) or cleft palate (fissure between the midlines of the upper lip or roof of the mouth), or cerebellar ataxia (uncoordinated motor skills).

The physician also will want to identify any irregularities of the penis, like abnormal curvature, hypospadias (underside opening of the urethra), or phimosis (too-tight foreskin over the glands).

Gynecomastia - over-development of the male breasts - is very suggestive of a hormonal imbalance that can affect fertility. Gynecomastia may be normal at certain stages of a man's life (at birth, adolescence and in old age). However, in disorders of the endocrine (hormonal) system, male breast enlargement may be due to low levels of the male sex hormone testosterone, high levels of the female sex hormone estrogen, or the use of particular medications.

Finally, the physician will want to check for other physical signs of hormonal malfunction. Thyroid disease may be suggested by thyromegaly (enlarged thyroid gland), thyroid nodularity ("knots" of tissue), or bruit (sound or murmur). Likewise, hepatomegaly (enlarged liver) may suggest other hormonal problems. A large percentage of men with liver cirrhosis (liver inflammation caused by alcohol or other factors) will have gynecomastia, impotence and atrophy (wasting away) of the testes (see also Risk Factors Associated with Male Infertility).

Lab Tests

Laboratory work-up of all male patients should include semen analysis, urinalysis (analysis of the urine), and, possibly, serum (blood) analysis.

Semen Analysis

Semen analysis is the most informative test for male infertility. It is not, however, a conclusive indicator of fertility versus infertility, since there is still some confusion about what is required for adequate and healthy ejaculate (expelled semen). And, more importantly, semen characteristics are not absolute predictors of sperm function. In spite of these limitations, guidelines - such as those of the World Health Organization (WHO) - have been established to determine semen quality limits below which the chance of achieving pregnancy becomes increasingly less likely (see Table 1). Thus, a semen sample with a sperm count of 50 million sperm per milliliter of ejaculate, 65% motility, and 60% oval morphology (shape) would be classified as "normal"; a semen sample with a low sperm count (less than 10 million/ml), poor forward motility, and 30% oval morphology would be less capable of producing a pregnancy.

A semen analysis should be repeated at least once and it may be a good idea to repeat semen analysis periodically as these levels can change over time.

What Does Semen Contain?

Besides containing sperm, normal semen contains a number of other substances. These substances include water; simple sugars like fructose that serve as nourishment for the sperm; alkaline chemicals that "buffer" the sperm against the acidic environment of the urethra and vagina; prostaglandins which are fatty acid compounds that spur contractions in the muscles of the uterus and fallopian tubes and are believed to aid the sperm's journey to the uterus/womb; vitamin C; zinc; cholesterol; and a few additional compounds. Although semen can carry the bacteria or viruses of STDs - including the AIDS virus , normal healthy semen does not contain any harmful substances.

The accuracy of semen analysis is enhanced by the use of proper collection methods. Before making any judgments about semen quality, it is customary for specialists to obtain at least three samples in which the semen characteristics are within the same 20% range. Ideally, the semen sample should be collected onsite at the physician's office, although an acceptable sample may be obtained at home as long as it is kept warm (at body temperature) during transit and is analyzed within 1 to 2 hours. Some specialists recommend that semen samples be collected after 1 full day of sexual abstinence (no sex for 24 hours after the last ejaculation), whereas others recommend a longer period of time (2 to 3 days, or 36-72 hours after the last ejaculation). It is very important to keep with the chosen abstinence schedule, because variations in the time period between ejaculations decrease the accuracy of test results. For up to 1 week, semen characteristics such as volume and sperm concentration increase with each day of abstinence; after that time, sperm motility (movement) may be impaired.

The semen specimen should be collected in a clean dry container supplied by the physician. If a patient objects to masturbation (self-stimulation) as a means of causing ejaculation for a semen sample, coitus interruptus (penis withdrawal during sexual intercourse) is another method that can be used to obtain a sample. If, because of religious or other beliefs, the patient objects to both masturbation and withdrawal, special untreated and/or perforated condoms can be used during sexual intercourse. Ordinary condoms should not be used for semen collection, since they may contain spermicides (substances that are toxic to sperm).

Semen volume - Semen volume usually affects fertility only when it is less than 1.0 ml or greater than 5.0 ml. A low semen volume (less than 1.0 ml) is unlikely to provide enough fluid to bring the sperm in contact with the female partner's cervix (womb) or to neutralize her vagina's natural acidic environment, which - while keeping bacteria under control - can kill sperm. A high semen volume (greater than 5.0 ml) may "dilute" the sperm and impede fertility. In such cases, methods can be used to concentrate the man's semen and reintroduce it to his partner's uterus via artificial insemination -injection of semen into the uterus via a syringe or similar device (see also Artificial Insemination).

Because the seminal vesicles and prostate contribute most of the bulk of ejaculate, a low semen volume may suggest a blockage (see also Anatomy & Physiology). A low semen volume also may suggest retrograde ejaculation (backward release of semen), infection or androgen (male sex hormone) deficiency. In addition, men with inherited absence of the vas deferens or seminal vesicles may have low semen volumes.

Sperm motility (movement) is the most important feature of semen quality. Motility is usually estimated by direct microscopic examination of the semen to determine what percent of the sperm are "swimming." New technologies now incorporate computer-assisted semen analysis (CASA) with video systems to measure the types and speed of sperm motility. These include curvilinear velocity (VCL), the average distance per unit time between successive sperm positions); straight-line velocity (VSL), the distance between first and last sperm positions per total elapsed time; linearity (VSL/VCL); and amplitude of lateral head placement (ALH), the average perpendicular distance of lateral positions of the sperm head in relation to the average path of swimming.

Structurally normal sperm swim faster and straighter than abnormal sperm. The average speed of human sperm is roughly 48-96 mm per second. The lower limit for VSL is 25 mm/sec, the lower limit for VCL is 40 mm/sec, and the lower limit for linearity is 5mm/sec. The quality of sperm movement is based on a classification system of 0 to 4, wherein 0 represents no movement and 4 represents excellent forward progression; for example, a semen sample with 60% motility would be characterized as "3+ to 4."

During motility testing, the laboratory will note any sign of sperm agglutination - the "clumping" of sperm during microscopic evaluation. Such clumping can keep the sperm from swimming properly through the cervical mucous and can prevent them from attaching to the egg. Increased agglutination may suggest an inflammatory condition (e.g., bacterial infection) or an immunologic abnormality. Sperm may "clump" head-to-head, tail-to-tail, or head-to-tail. In particular, tail-to-tail agglutination of motile sperm is noteworthy and usually is followed up with tests for antisperm antibodies (see also Other Tests of Sperm Function). Sperm morphology, or sperm shape, is determined by an average scoring of at least 100 cells.

Sperm morphology is considered within the normal range if more than 50% of the sperm have an oval head, a length of 3 to 5 mm, and a width of 2-3 mm, with a customary mid-piece and tail. Some specific forms of sperm abnormalities include small or enlarged heads, coiled tails, duplicate heads, immature sperm shape, and sperm with absent or multiple nuclei (see also Toxins in the Workplace). A newer system called strict morphology is more stringent, with 15% the lower limit of normalcy.

Semen viscosity, known as liquefaction (liquid flow), also affects fertility. For example, in normal men, ejaculated semen coagulates (gels) and then liquefies within 20 to 30 minutes. If liquefaction is delayed more than 60 minutes, the sperm may become trapped in a jelly-like mass. Since the prostate gland produces the substance needed for liquefaction, nonliquefying semen may signal a disorder of prostate gland function (for example, prostate infection).

Semen analysis may reveal a number of signs suggesting cell debris or infection. The presence or absence of cell forms in the semen (germ cells [immature sperm], blood cells, bacteria, protozoa) may indicate specific disorders that can affect potency. For example, numerous germinal cells, along with debris from dead or immotile (nonmoving) sperm, may suggest recent testicular stress due to fever-related illness or infection (e.g., a severe episode of the flu). In such cases, after a few months of recovery, sperm characteristics usually return to normal. Too many leukocytes (white blood cells) - greater than 5 million/cc - may imply a fertility-hampering infection in either the male patient and/or his female partner. STDs, such as gonorrhea or ureaplasma, usually are treated in both individuals and respond well to antibiotic therapy with doxycycline, a tetracycline derivative. Prostate infections also can be managed by antibiotic therapy, although such infections tend to "hang on" and may take over a month to completely resolve (see also Medical Management of Infertility).

If a man's semen lacks fructose (sugar), fails to gel, and has a low volume, he may suffer from an inherited absence of the vas deferens and seminal vesicles, or he may have a blockage in the ejaculatory ducts.

Other Sperm Tests

The postcoital test, otherwise known as the Sims-Huhner or sperm-mucus interaction test, examines whether the sperm are able to complete their passage through the female partner's reproductive tract. This test is conducted during the middle, ovulation (egg-releasing) period of the woman's monthly cycle. At this time, her cervical mucus - which normally acts as a barrier that seals the womb from the outside - is thin and watery so that the sperm are better able to swim through the cervix and fertilize the awaiting egg.

Prior to postcoital testing, an ovulation test kit usually is employed to determine the exact day of ovulation (a few drops of the woman's urine are placed on a test stick; a color change in the stick will indicate that ovulation should occur within the next 24 hours). Intercourse is recommended that evening, and the postcoital test is conducted on the following morning. In brief, the physician will inspect the female's cervical mucus to see whether:

· enough semen was delivered to the cervix

· sperm are healthy and do not show large numbers of clumped, motionless or dead cells

· sperm are swimming energetically through the cervical mucus.

If no sperm are found in the cervical mucus, but they are present in the vagina, hostile vaginal factor or sperm factor may be suspected, especially if the man's semen analysis is normal. In such cases, the woman may be inseminated with washed sperm to overcome such factors and to help the sperm to pass into the cervix. If many "shaking," motionless, clumped or dead sperm are found in the cervical mucus, the sperm and mucus may be incompatible, or something in the mucus may be attacking the sperm.

Reactions can be caused by external factors, such as the use of vaginal lubricants, or by internal factors, such as an allergic response to the sperm by the woman or the production of antisperm antibodies by the man (e.g., men who have had recurrent STDs or undergone a vasovasostomy for vasectomy reversal; see also Vasovasostomy).

The sperm penetration assay (SPA) - also known as the sperm-oocyte interaction test or zona-free hamster egg test - examines the ability of a man's sperm to penetrate the cell membrane of a hamster egg, which is anatomically similar to a human egg. The assay is a simple, "test tube" experiment in which hamster eggs and a semen sample are combined in a dish. Later, the eggs are checked for penetration by the sperm. A penetration rate of greater than 10% is good evidence of the fertile potential of the sperm, whereas a penetration rate of less than 10% my indicate less-than-adequate fertility. Men with low sperm counts and normal follicle-stimulating hormone (FSH) levels make up the largest subset of the infertile male population. For these men, SPA tests can help physicians to determine the fertilizing potential of the sperm and thus to decide upon appropriate medical therapy (see also Medical Management of Infertility).

The immunobead test is used to detect the presence of antisperm antibodies that may lessen the fertilizing potential of sperm. Antibodies are immune system molecules that interact with the specific antigens (foreign substances, such as proteins, toxins, or bacteria) that caused them to be manufactured by the body. Antisperm antibodies can interfere with the physical changes that the sperm must undergo to successfully swim through the cervical mucus and penetrate the egg for fertilization.

The immunobead test, which is conducted in vitro (in a test tube), uses tiny polyacrylamide "beads" that are coated with specific antibodies. These antibodies, in turn, bind to antisperm antibodies and identify any classes of immunoglobulins (an immune system protein with antibody activity; classes are abbreviated as "IgG", "IgA," etc.) that may be present. The immunobead test can distinguish the location on the sperm where the antibody is located (head, mid-piece or tail). There are two types of immunobead testing. The first, direct method measures the binding of beads to the target sperm surface. The second, indirect (passive) method includes an additional procedure in which antibody is transferred to the donor sperm from the body fluid in question (cervical mucus, follicular fluid, blood or semen).

Antisperm antibodies have been found in some men who have undergone vasovasostomy (see also Vasovasostomy). Antisperm antibodies also have been found in men who have experienced other forms of genital injury - such as testicular trauma, testicular torsion (twisting), or repeated STDs, - as well as improper descent of the testes, orchitis (inflammation of the testes), and long-term pyospermia (increased numbers of white blood cells in the sperm).

Current approaches to the treatment of antisperm antibodies include methods of sperm processing to remove surface antibodies, such as rapid washing, freeze-thawing and enzyme cleavage. All of these methods have modest, if any, success rates. In vitro fertilization (IVF), with or without sperm processing, may provide a better alternative for couples with positive immunobead tests (see also In Vitro fertilization).

Other Tests

Urinalysis

Urinalysis - the testing of urine - is an important part of the infertility work-up, because it may reveal unsuspected, fertility-impairing disorders such as kidney disease or diabetes. In addition, urinalysis will be able to detect lower urinary tract infections (UTIs) that cause urethritis (inflammation of the urethra) and cystitis (inflammation of the bladder). Some infertile men may notice that they achieve orgasm without much ejaculate ("dry ejaculation") or that they have cloudy urine after ejaculation. In such individuals, urinalysis immediately after ejaculation may help to diagnose retrograde ejaculation - backward release of semen into the bladder (see also Retrograde Ejaculation).

Serum (Blood) Tests - Endocrine Testing

If after taking a careful history and physical examination, the physician suspects that infertility is caused by an endocrine (hormonal) problem - for example, in cases in which the sperm density is very low or there are specific signs of hormone imbalance - he or she may want to conduct blood tests to measure levels of reproductive hormones. Yet, it should be noted that fewer than 3% of cases of male infertility are caused by primary endocrine defects.

Blood tests known as radioimmunoassays (RIAs) are used to measure levels of the hormones testosterone (male sex hormone or "androgen"), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (see also Normal Process of Sperm Development and Endocrine Disorders). Testosterone, which is produced by the Leydig cells of the testes, is directly regulated by LH, a secretion of the pituitary gland. LH, in turn, is controlled by gonadotropin-releasing hormone (Gn-RH), which is produced by the hypothalamus. Prolactin, another pituitary hormone, affects Gn-RH release from the hypothalamus. Thus, these reproductive hormones interact with each other in an intricate balance.

Serum testosterone level usually is low in men with hormone-related hypogonadism (delayed sexual maturity) and in men with abnormal Leydig cell function in the testes. These men often have a history of reduced libido and impotence. Yet total testosterone levels can be misleading. For example, men with testicular failure (as in alcohol-related cirrhosis or Klinefelter's syndrome) may have testosterone levels that are "within the normal range" because of an increase in estrogen-induced, testosterone-binding globulin (TeBG). In such individuals, testicular failure must be confirmed by increased blood levels of FSH and LH, along with testicular atrophy (see Table 2), as well as by checking testosterone levels.

Although not routinely performed, blood levels of estradiol (a form of estrogen) may be measured in men with gynecomastia, and prolactin levels should be measured in men who are infertile, complain of sexual dysfunction, and/or show signs of pituitary disease. Thyroid hormone testing is unnecessary unless the patient has a history or evidence of thyroid disease. Likewise, routine measurement of adrenal steroids is unnecessary unless the patient shows signs of adrenogenital syndrome.

Testis Biopsy

Sometimes azoospermia - a lack of sperm in the semen - will occur in a man with apparently normal testes and vas deferens structures. The patient also may have normal levels of reproductive hormones for example, normal testosterone and follicle-stimulating hormone (FSH). In this case, the physician will want to perform a testis biopsy. The biopsy will reveal whether or not the lack of sperm is due to testicular failure (no functional, sperm-producing tissue) or obstruction of the pathways from the testes to the urethra. Azoospermia in a man with soft, small testes and a borderline FSH level is very likely to be caused by testicular failure. In this instance, a biopsy is needed only when confirmation is absolutely essential.

If the man's semen is fructose-positive, the physician may assume that there are no major obstructions in the ejaculatory ducts. Fructose, the energy-supplying sugar found in semen, is made in the seminal vesicles. Men who are born without the vas deferens tubes have no seminal vesicles and, therefore, no fructose in their semen. Fructose also is missing in men with bilateral ejaculatory duct obstruction. Fructose-negative semen does not coagulate after ejaculation. Yet, fructose-positive semen does not necessarily ensure a totally obstruction-free (patent) path out of the body. So, in addition to testis biopsy, vasography - an X-ray study in which dye is injected into the vas deferens - is sometimes recommended to rule out obstruction (see also Vasography).

Open testis biopsy - a surgical biopsy that allows visualization of the exposed structures - is the preferred method of testis biopsy. This procedure generally is performed in a hospital, and the patient is given local or general anesthesia. A "window technique" is used when a simple biopsy is planned and no inspection of the epididymis is necessary. The frontal skin of the scrotum is stretched, the testis is lifted, and a small incision is made through the surrounding membrane sheath. Gentle pressure then is applied to squeeze out a small amount of testicular tissue, which is excised (cut out) and placed in an appropriate preservative solution. Both testes should be biopsied if there are indications of ductal obstruction or testicular failure.

Customary tissue preparation techniques - such as fixation in formalin, embedding in paraffin, and staining by hematoxylin and eosin - are not recommended for testis biopsy samples. Instead, newer methods are endorsed, such as fixation with glutaraldehyde, embedding in plastic, and the use of high-resolution microscopy techniques.

Percutaneous testis biopsy is another procedure that may be used to obtain a tissue sample from the testis. Performed under local anesthesia with a special cutting device, this method is a "blind" technique that does not permit the physician to see within the testis itself. Because of this, there is a risk of unintentional injury to either the epididymis or testicular artery. In addition, some specialists criticize the quality of percutaneous biopsy samples. Therefore, many physicians do not recommend percutaneous biopsy for testis sampling.

Fine-needle aspiration biopsy employs a fine-gauge, or small diameter, needle that draws out (aspirates) cellular material from the testis. Methods such as flow cytometry (a cell-counting device) then are used to analyze the sample. Testicular aspiration causes minimal injury to the testes. However, some physicians believe that uniform standards have not been developed to accurately interpret the results of aspirated biopsy samples.

The following terms often are used to describe testis biopsy results:

Hypospermatogenesis or germ-cell hypoplasia - slow rate of sperm production. This may be due to reduced activity and/or loss of the "germ cells" that eventually mature to become sperm. Causes of hypospermatogenesis include toxins, drugs and varicoceles (see also Causes of Infertility and Risk Factors Associated with Infertility).

Maturation arrest - stopping of sperm development. This is a common biopsy result. The germ cells are found to divide and produce early forms; however, at some stage of sperm development, maturation stops throughout the testicular tubules. Maturation arrest may be complete, as in azoospermia (no sperm in the semen), or partial, as in oligospermia (low sperm count in the semen). Causes of maturation arrest include toxins, drugs and varicocele (see also Causes of Infertility and Risk Factors Associated with Infertility). Sperm production often can be restored in a patient with maturation arrest and a low or normal level of follicle-stimulating hormone (FSH). Unfortunately, maturation arrest in a patient with a high FSH level usually signals severe, untreatable testicular damage.

Germ cell aplasia or Sertoli cell-only syndrome - the seminiferous tubules are lined only by Sertoli cells. The germ cells are not developed in affected patients; therefore, sperm cannot be produced. Causes of germ-cell aplasia include exposure to toxins, chemotherapy or radiotherapy, although most cases are caused by unknown factors.

Tubular/peritubular sclerosis - hardening of the interiors of the seminiferous tubules and surrounding tissues. In tubular sclerosis, there are no cells lining the hardened seminiferous tubules, and the Leydig cells (testosterone-producing cells that lie around and between the seminiferous tubules) may be missing. Affected men may have small testes and high levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In some instances, tubular sclerosis may suggest Klinefelter's syndrome.

Radiologic Tests

Radiologic tests - tests that use X-ray methods and contrast media - may be needed to help the physician "see" blockages within the ductal system of the scrotum.. Radiologic tests are particularly important for men who are azoospermic (lack sperm in the semen) but have normal sperm production (spermatogenesis).

Vasography is an X-ray study in which dye is injected into the vas deferens. The procedure usually is conducted under general anesthesia. A small vertical cut is made over the testis, which is then pulled forward. (Note: If the patient has a history of inguinal [groin] hernia repair, the cut may be made directly over the scar from the previous surgery; sometimes the obstructed site of the vas is clearly found at this site and vasography is not even necessary.) The vas deferens is identified and, using an operating microscope and microsurgical tools, the cavity (lumen) of the vas is inspected for the presence of sperm-containing fluid. If no fluid is present, a catheter (flexible tube used to withdraw fluid) is passed through the vas to the epididymis, which is "milked" for fluid. If there is still no fluid, the seminal vesicle end of the vas is filled with a salt water and/or dye solution to confirm that this region is free from obstruction.

· If a large amount of sperm-containing fluid is present when the lumen of the vas deferens is opened, there is probably a blockage in the seminal vesicle end of the vas. A catheter is passed up through the vas and is filled with water-soluble dye and contrast media (substance that is visible on X-ray); the procedure is then repeated with the vas on the other side.

· If a blockage is found at the ejaculatory ducts, surgical correction is performed at this time.

· If the vas deferens ends blindly, far away from the ejaculatory ducts, no further surgery is performed.

· If a blockage is found in the inguinal (groin) region, the physician will conduct an inguinal vasovasostomy to surgically connect the unobstructed portions of the vas deferens (see also Vasovasostomy).

· If there are no sperm in the fluid from the vasography site, and there is no blockage at the seminal vesicle end of the vas, the vas may be cut and readied for vasoepididymostomy - a new, surgically made connection between the vas deferens and the epididymis.

After vasography, microsurgical methods are used to close the operative site. It is not uncommon for scrotal exploration to be performed at the same time as vasography, since physicians want to be able to find and, if possible, correct any physical obstructions or other abnormalities noted during one surgery.

Physical Causes of Male Infertility

As previously described, four factors govern male fertility: hormones, sperm production, the ductal system of sperm delivery, and sexual function. Among these factors, physical variables that affect the structure of the testes are particularly important.

Cryptorchidism

Cryptorchidism, also known as cryptorchism, is the failure of one or both testes to descend (move down) into the scrotum. The descent usually is complete at birth or by the end of the first year of life. However, if the testes do not drop and remain in an upper, abdominal location, spermatogenesis (sperm production) and, correspondingly, fertility, usually is impaired. Unilateral (one-sided) cryptorchidism is associated with oligospermia (low sperm count), whereas uncorrected, bilateral (two-sided) cryptorchidism usually is associated with azoospermia (no sperm in the semen). Researchers believe that the increased temperature within the abdomen harms the enzymes and proteins that are responsible for normal sperm production. Sperm quality may be especially poor in men who have bilateral undescended testes.

Cryptorchidism is a common childhood disorder. Undescended testes have been reported in roughly one-third of preterm babies and 3% of full-term babies. These figures are evidence of the late occurrence of testes descent during fetal growth within the womb. Yet incomplete testicular descent is not just a physical abnormality. Other disorders, such as infertility and testicular cancer, may be a consequence of cryptorchidism (see also Testicular Tumors). Fertility appears to improve among men who receive therapy for cryptorchidism before puberty.

Most cryptorchidism cases have no known cause. The physician should suspect a history of cryptorchidism if:

· the patient has an old incision over the groin,

· the testis cannot be felt in the scrotum, or

· the testis is very soft and small.

Most undescended testes can be classified into three different categories:

· True undescended testes are positioned within the normal route of descent but cannot manually be lowered into the scrotum.

· Retractile testes usually occur between the ages of 3 and 6 years due to hyperactivity of the cremasteric muscles (abdominal muscles that elevate the testes).

· Ectopic (displaced) testes are positioned outside the normal route of descent, in areas such as the upper groin, floor of the pelvis, penile shaft or thigh.

Note: many researchers believe that the tendency for cancer development in ectopic testes is less than that in true undescended testes.

Now to treat cryptorchidism - surgically or with hormonal therapy - is a subject of much controversy among doctors. Yet most experts recommend some form of therapeutic management between the child's first and second birthdays. In the United States, a preferred approach to therapy for unilateral cryptorchidism is surgical placement of the testis in a normal scrotal position before the second birthday.

For bilateral cryptorchidism, many specialists use a combination of surgery and hormone therapy with human chorionic gonadotropin (HCG) and/or gonadotropin-releasing hormone (Gn-RH). By contrast, European physicians generally rely on hormone therapy as the primary treatment for all patients with cryptorchidism.

Unfortunately, once the testes have been injured by cryptorchidism, such injury usually cannot be corrected. Since men with cryptorchidism are more likely to have hormone abnormalities or malformations of the testicular ducts, infertility management may focus upon these factors. In particular, some physicians report improvements in sperm quality among men who receive medical therapy with clomiphene citrate (an anti-estrogen drug) and human chorionic gonadotropin (HCG). Patients with low sperm counts may benefit from assisted reproductive technologies (ART) such as in vitro fertilization (IVF), artificial insemination using the husband's sperm (AIH), artificial insemination using donor sperm (AID), gamete intrafallopian transfer (GIFT), or intracytoplasmic microinjection of human sperm into a human egg (ICSI)

Testicular Tumors

The rate of testicular tumor is especially high among men with undescended testes. Therefore, hormone therapy and/or orchiopexy (surgical placement of an undescended testis in the scrotum) is advisable in most instances (see also Cryptorchidism). Even though the increased risk of cancer remains after such treatment, the testes are more easily examined for potential malignancies when they are in the scrotal position.

Infertility problems are common among men who have been treated for cancer. Chemotherapy with alkylating agents (such as cyclophosphamide, chlorambucil and mustine) is very toxic to the tissue that gives rise to sperm cells. Men with testicular cancer are especially affected, and they often decide to undergo "sperm banking" (the collection and freezing of sperm) before beginning chemotherapy or other procedures (see also Neurogenic Causes and Assisted Reproductive Technologies).

In addition, the cumulative effects of radiation therapy can significantly lessen fertility. If radiation is to be used to treat a testicular or abdominal region tumor, the extent of the radiation dose should be examined carefully. The seminiferous epithelium of the testes may be damaged if the radiation dose approaches the range of 600 to 800 rad (see also Radiation).

Testicular tumors sometimes occur in association with inherent overgrowth of the adrenal glands above the kidneys, otherwise known as congenital adrenal hyperplasia (CAH) (see also Endocrine Disorders). It is believed that some adrenal cells may become misplaced within the testicular tissue during fetal development. When the secretion of adrenocorticotropic hormone (adrenal-stimulating hormone; ACTH) begins, these cells may start to overgrow and may appear as testicular tumors. However such tumors, which respond to glucocorticoid therapy, should be differentiated from Leydig cell tumors, another form of testis tumor. Leydig cell tumors usually require castration for appropriate management, whereas adrenal cell tumors do not.

Testicular Trauma

Injury of the testes may result in male infertility, especially if the trauma is followed by a reduction in the size of the injured testicle and/or the detection of antisperm antibody in the man's semen. It is believed that such infertility results not from the wasting of testicular tissue, but rather from an immune reaction that occurs due to penetration of the Sertoli cells' "blood-testis barrier" in the testes.

Testicular trauma may be caused by physical impact, by torsion (twisting), or by damage that takes place on a cellular level, such as occurs with repeated infection with STDs. Research suggests that a torsion-prone testicle may have inherent defects in its sperm-producing potential, as shown by findings of impaired spermatogenesis in tissue samples from the opposite testicle.

Varicocele

Varicocele - varicose veins of the scrotal venous system that drains the testicles - is a common abnormality found in roughly one-third of all men who are being evaluated for infertility. And, although not all men with varicoceles are infertile, a significant number of infertile men will have a varicocele.

Varicocele is caused by a back-flow and pooling of blood due to malfunctioning or missing valves in the spermatic veins. Because of the long, top-to-bottom route of the internal spermatic vein (ISV) on the left side of each testis, over 90% of varicoceles occur on the left; therefore, a right-sided varicocele may indicate the presence of another disorder, such as a venous blood clot or tumor.

How Does Varicocele Cause Infertility?

Many theories have been proposed. To date, the most widely accepted mechanisms include sperm death due to:

· hyperthermia (high temperature) in the scrotum because of stagnant venous blood;

· reflux (backflow) of venous blood from the left adrenal gland, which exposes the testes to high levels of toxic metabolites (steroids, catecholamines); or

· changes in the reproductive hormonal balance.

To properly identify a varicocele, the physician should examine the patient while he is standing. The cord structures will be palpated (felt) and compared. Then, the patient may be asked to perform a Valsalva maneuver (a forced "exhale" with a closed nose and mouth), which will increase venous reflux and make an existing varicocele more prominent. Additional palpation of the scrotum will be conducted while the patient is supine (lying down). The physician may confirm a diagnosis of varicocele using Doppler ultrasound testing (visual imaging of internal organs by means of ultrasound echos that identify tissue density changes and compare them with the speed of blood flow in underlying vessels). If clinical and Doppler studies are inconclusive but suggestive of a varicocele, venography (X-ray of a vein filled with contrast medium) may be employed.

Varicoceles often are managed by varicocelectomy (video) - the surgical "tying off" of the affected spermatic veins. Varicoceles that are identified during venography can be treated by embolization (sealing off with a blood clot) using devices such as a steel coil, balloon catheter and/or sclerosing solutions. Both methods may be performed on an outpatient basis; using regional or local anesthesia.

Sexually Transmitted Diseases (STDs)

Infections of the male genital tract may impair fertility. For example, diseases such as gonorrhea, tuberculosis and the more common gram-negative bacteria of the urinary tract may cause inflammatory changes of the ductal system and produce blockages within the epididymis or vas deferens. In particular, large amounts of the gram-negative bacteria E. coli may hinder sperm motility and cause the death of immature sperm cells. Chronic bacterial infection of the semen may be an unsuspected factor in male infertility.

Other diseases, such as mumps and syphilis, can cause orchitis (inflammation of the testes), which is characterized by severe interstitial edema (swelling between the tissues), increased numbers of mononuclear leukocytes (white blood cells), and possible irreversible damage of the seminiferous tubules.

Some experts dispute the fertility-impairing potential of mycoplasma hominis infection, whereas others report improved pregnancy rates among infertile couples who have received appropriate antibiotic therapy for mycoplasma. Infectious organisms such as Chlamydia trachomatis, Ureaplasma urealyticum, herpes, and cytomegalovirus also may cause urethritis (inflammation of the urethra), epididymitis (inflammation of the epididymis), and semen with few and/or abnormal sperm; however, researchers have not confirmed the contribution of these organisms to reproductive failure.

Systemic Illness

Not much is known about the overall effects of illness on testicular function. Specific questions remain about how diseases, metabolism and therapeutic drugs may affect reproductive function. Yet fever alone has been shown to damage sperm. In humans, high temperatures may kill or injure sperm cells after only a few hours. The resultant decrease in sperm count often appears within 3 weeks after an episode of high fever and can last for as long as 1 months. In addition, the characteristics of the sperm itself may be changed, showing more abnormal shapes and immature cells.

Men with systemic illnesses such as kidney disease, liver disease, and sickle cell disease often have abnormal levels of reproductive hormones. In particular, uremia (high levels of urea and other metabolic byproducts in the blood) due to kidney failure is associated with decreased libido, impotence, gynecomastia, and decreased spermatogenesis (sperm production). Reproductive hormone levels are especially disturbed in patients who must undergo repeated hemodialysis. Such abnormal hormone levels ultimately may result in reduced sperm production. In addition, researchers have documented changes in semen quality following allergic reactions or emotional disturbances.

Duct Obstruction

If a man is found to have normal levels of reproductive hormones and a normal testis biopsy, yet his semen does not contain sperm and it is fructose-negative, then the physician should consider the possibility of ejaculatory duct obstruction (video) due to inherent or inflammatory causes. Repeated urinary tract infections (UTIs) - as experienced by men with spinal cord injuries - may lead to inflammation of the prostate or epididymis which, in turn, may lead to ductal obstruction. In addition, vasectomy - a contraceptive procedure in which the vas deferens is cut - is now the leading cause of infertility due to ductal obstruction in men who have undergone vasectomy reversal procedures.

If ductal obstruction is suspected, the physician may examine the scrotum by vasography (see also Vasography). Resection (surgical maneuver) of the ejaculatory duct area may relieve the blockage, especially in men with inherent obstructions or absence of the ejaculatory ducts (see also Surgical Management of Infertility). Obstructions due to infections often are more difficult to manage, since inflammatory lesions may be extensive and associated with much scarring. If it is not possible to surgically correct the obstruction, then reproductive assistance is a potential option, for example, collection of epididymal sperm and in vitro fertilization (IVF).

Retrograde Ejaculation

The process of ejaculation depends upon the normal function of the bladder neck. A variety of abnormal conditions may interfere with the bladder neck's nerves and/or muscles, preventing its closure and leading to the backwards, "retrograde" flow of semen into the bladder.

Men with retrograde ejaculation may experience symptoms such as "dry ejaculation" and cloudy urine after ejaculation. But often the first sign of retrograde ejaculation is noticed during an infertility work-up, when semen analysis identifies the man's ejaculate as being acidic, low-volume (less than 1 ml), oligospermic (low sperm count), or azoospermic (no sperm in the semen). Postejaculation urinalysis also may detect a large amount of sperm in the patient's urine.

Retrograde ejaculation may result from surgical procedures performed upon the bladder neck, prostate, pelvis, pelvic lymph nodes, or colon, among other abdominal sites. In particular, "Y-V plasty," a surgical procedure that was performed in the 1950s and 60s to repair the bladder neck, has resulted in a high incidence of retrograde ejaculation among the men who were so treated as boys. Retrograde ejaculation also is caused by damage to the sympathetic nervous system which affects the bladder neck and by narrowing of the urethra due to injury. Diabetes mellitus - and its associated nervous system malfunction - is responsible for a number of ejaculatory disorders, including retrograde ejaculation.

In addition, a variety of medications have been linked to retrograde ejaculation. A common feature of such medications is their tendency to disrupt the normal activity of the sympathetic nervous system (smooth muscle system of the lower body). In particular, drugs for hypertension (high blood pressure), as well as alcohol, methadone and psychotropic medications - tranquilizers, antipsychotics, antidepressants - can affect the emission and ejaculation of semen.

The treatment of retrograde ejaculation includes methods to recover the live sperm from the bladder. Patients are instructed to alkalinize (de-acidify) their urine by drinking sodium bicarbonate solutions several days prior to semen collection. Then the urine is collected after ejaculation, and separation and "sperm washing" techniques are used to gather the live sperm. Finally, the sperm are placed in the female partner's cervix by artificial insemination.

In men with retrograde ejaculation due to neurologic causes, drug therapy with sympathomimetics - medication that mimics activity of the sympathetic nervous system may be successful. In addition, corrective surgical procedures, such as plastic reconstruction of the bladder neck or removal of scar tissue, may be beneficial for men in whom retrograde ejaculation is the result of anatomical abnormalities.

Neurogenic Causes

Men who survive testicular tumors frequently experience fertility problems because of the side effects of treatment by chemotherapy, radiation therapy, and/or retroperitoneal lymph node dissection (RPLND) (see also Testicular Tumors). RPLND, in particular, can cause neurogenic (nervous system-related) dysfunction that leads to retrograde ejaculation. The standard RPLND procedure involves the interruption of the sympathetic nervous system chain or its long nerves (e.g., the sacral plexus and hypogastric nerves), which results in nerve damage. Fortunately, however, updated RPLND procedures are "nerve sparing" and produce fewer cases of abnormal ejaculation. Men who experience retrograde ejaculation after RPLND sometimes respond favorably to treatment with sympathomimetic drugs like ephedrine sulfate.

The fertility rate in men with spinal cord injuries is estimated to be less than 5%. The reasons for such infertility include: neurogenic dysfunction that alters or inhibits semen ejaculation, inability to achieve and sustain an erection for vaginal intercourse, insufficient sperm production, and reduced occasions for sexual contact. Yet fertility may be improved by a variety of techniques in spine-injured men with neurogenic retrograde ejaculation. Sympathomimetic drugs, such as ephedrine, pseudoepinephrine and phenylpropanolamine, rarely help to produce ejaculation. But if drug therapy fails, semen samples may be obtained for artificial insemination or in vitro fertilization (IVF) by other means, such as vibratory stimulation of the penile corona (rim of the glands), electroejaculation (a rectal electrode is used to stimulate ejaculation), or injections with nerve-activating agents, such as cholinergic drugs like neostigmine (spinal injection) or physostigmine (skin injection). Because of the retrograde nature of ejaculation in many men with spinal injuries, the bladder should be catheterized (a flexible tube inserted to withdraw fluid) and the urine collected after ejaculation. Urine separation and "sperm washing" techniques then may be used to gather the live sperm for artificial insemination or IVF procedures (Note: sperm quality often is not as good in men with indwelling catheters and in those who practice high-pressure urination). If none of these methods successfully produce ejaculate, the physician may use microsurgical techniques - surgery that uses a microscopic camera and very small operative tools - to remove sperm directly from the vas deferens or epididymis (see also Assisted Reproductive Technologies).

The female partners of spine-injured men may need to be treated with ovulation-stimulating agents, to optimize clinical success. Therefore, the man's urologist and his partner's gynecologist should work together to ensure that all fertility procedures are conducted at the optimal times to achieve pregnancy.

Endocrine Disorders

Most endocrine causes of male infertility are due to a lack of sufficient levels of "gonadotropic" - gonad (sex gland)-stimulating - hormones. Endocrine disorders may be caused by deficiencies in one or a number of interdependent sex hormones.

Normal reproductive function is controlled by a feedback mechanism known as the hypothalamic-pituitary-gonadal axis. This hormonal "loop" connects the activities of the pituitary (gland at the base of the brain), hypothalamus (pituitary-linked organ), and the testes. The front of the pituitary gland secretes the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In turn, the pituitary is controlled by the hypothalamic secretion of gonadotropin-releasing hormone (GnRH). Finally, the testes produce the steroid hormone testosterone, which is a principle preventer of LH secretion.

Testosterone is broken down in peripheral tissue to form the androgen (male sex hormone) dihydrotestosterone (DHT) and the estrogen (female sex hormone) estradiol - both of which also modulate LH secretion (see also Normal Process of Sperm Development).

Secondary Hypogonadism (Hypogonadotropic Hypogonadism)

A lack of gonadotropin-releasing hormone (GnRH) - or deficiencies in pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) - can produce a variety of conditions defined as secondary hypogonadism or hypogonadotropic hypogonadism (delayed sexual maturity due to sex hormone deficiency). These disorders are usually inherited and are linked with abnormalities of the nervous system, genitals, and other body parts. One notable abnormality is anosmia - lack of sense of smell.

Unlike the untreatable infertility caused by primary hypogonadism, infertility caused by secondary hypogonadism often is manageable by appropriate hormone therapy.

Isolated Gonadotropin Deficiency

Otherwise known as Kallmann's syndrome, isolated gonadotropin deficiency is a genetically inherited disorder that affects the function of the hypothalamus (pituitary-linked organ). The features of Kallmann's syndrome include microphallus (small-sized penis) and/or cryptorchidism (undescended testes) during childhood. However, the most notable characteristic of Kallmann's syndrome is delayed puberty. Other Kallmann's syndrome "clues" are a positive family history of the disorder, anosmia, and "midline" defects such as hare lip, cleft palate and facial asymmetry.

Affected adolescents may exhibit normal growth curves, with a height-age greater than bone-age and testes that are smaller than 2cm in diameter. Although pre-pubertal LH and FSH levels may be within the low-normal range, serum testosterone levels will be low. The GnRH stimulation test will produce an increase in both LH and FSH.

Isolated LH Deficiency

Otherwise known as fertile eunuch syndrome, isolated LH deficiency is notable for the "eunuchoid" features that are present in affected men. Such features include a preadolescent distribution and density of body hair; poor skeletal muscle development, and non-closed epiphyses (ends of the long bones), resulting in an unusually long arm span and long lower body segment. LH-deficient individuals often have large testes, but variable secondary sexual characteristics, with or without gynecomastia (overdevelopment of the male breasts). Fertile eunuch syndrome is caused by malfunction of the pituitary gland.

Men with fertile eunuch syndrome may have normal FSH levels, but low-normal blood levels of LH and testosterone. The administration of human chorionic gonadotrophin (HCG) will cause an increase in testosterone level, but testing with clomiphene citrate (an LH-stimulating agent related to estrogen) will not spur an increase in the blood level of LH. Afflicted men may have enough LH-stimulated testosterone to induce sperm production, but they won't have enough testosterone to complete the development of male secondary sex characteristics. Treatment with human chorionic gonadotropin (HCG) may successfully produce complete virilization and spermatogenesis in men with partial LH deficiency.

Hyperprolactinemia or Postpubertal Gonadotropin Deficiency

Gonadotropin shortage in a sexually mature man usually is the result of a pituitary tumor, which influences the secretion of the gonadotropins LH and FSH. A tumor, whether small (microadenoma; less than 10 mm) or large (macroadenoma; greater than 10 mm), may cause excess secretion of prolactin, a hormone produced by the front of the pituitary. Affected men may experience a loss of libido (sexual desire), reduced potency, gynecomastia (overdevelopment of the male breasts), galactorrhea (spontaneous milk flow), and altered sperm production. Also, they may produce particularly small amounts of ejaculate, due to abnormal function of the Leydig cells (testosterone-producing cells) within the testes. In addition, pituitary insufficiency can result from other, less common factors such as pituitary damage from surgery or radiation.

The signs of postpubertal gonadotropin deficiency may arise years before any other symptoms of pituitary tumor (i.e., headache, changes in the visual field, or low levels of thyroid and adrenal hormones) . If the pituitary tumor is long-standing (5 to 10 years), the patient eventually may begin to lose secondary sex characteristics, and the testes may become small, soft and atrophied (shrunken). Blood testosterone level will be below normal, gonadotropin levels will be low/low-normal, and testis biopsy will show a lack of mature Leydig cells. In addition, men with postpubertal gonadotropism may have below-normal blood levels of corticosteroids, thyroid-stimulating hormone (TSH), and growth hormone.

Men with suspected tumors should undergo scanning by CT (computerized tomography) or MRI (magnetic resonance imaging), and they should undergo functional laboratory testing of the anterior pituitary, thyroid and kidney. Since prolactin release is governed by the catecholamine dopamine, the dopamine-like medication bromocriptine will reduce prolactin levels and restore normal gonadal function in men with prolactin-secreting tumors (see also Drug Therapy). The customary therapeutic dose is 5-10 mg daily.

Congenital adrenal hyperplasia (CAH)

An uncommon inherited disorder that may be associated with a lack of 21-hydroxylase - an enzyme found in the adrenals (glands above each kidney). Hyperplasia (overgrowth) of the adrenals leads to excessive production of adrenal testosterone that, in turn, inhibits the release of pituitary gonadotropin.

Early puberty and short stature (height) are hallmarks of CAH. However, congenital adrenal hyperplasia is difficult to diagnose, since affected men often appear "normal" and sexually mature, without excessive masculinization. Men with CAH often will show low/normal blood levels of adrenal steroid compounds, such as cortisol. In addition, they may have low/normal urinary levels of 17-hydroxycorticoid and high urinary levels of 17-ketosteroids and pregnanetriol (a byproduct of the pregnancy hormone progesterone). Testicular tumors sometimes are detected in men with CAH (see also Testicular Tumors).

Dexamethasone may be used to suppress adrenal secretion in men with CAH. In addition, glucocorticoid therapy may provide fertility benefits in men with CAH by increasing sperm output.

Prader-Willi Syndrome

An inherited, secondary hypogonadism disorder. Affected male infants may show reduced muscle tone at birth. Some of the distinguishing features of Prader-Willi syndrome include small testes, diminished mental capacity and obesity. It is believed that the disorder is caused by a defective mechanism of gonadotropin-releasing hormone (GnRH) secretion by the hypothalamus.

Infertile men with Prader-Willi syndrome may benefit from hormone therapy. Specifically, blood testosterone levels may increase following human chorionic gonadotrophin (HCG) administration, and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels may increase in response to chronic GnRH therapy.

Lawrence-Moon-Biedl Syndrome

Also an inherited disorder. Like Prader-Willi syndrome, the hypogonadism in Lawrence-Moon-Biedl syndrome is believed to be caused by a hypothalamic deficiency of GnRH. This disorder is associated with a number of additional abnormalities, such as mental retardation, extra fingers and/or toes (polydactyly), and retinitis pigmentosa (hereditary eye diseases in which there is progressive loss of sight).

Hemochromatosis

A disorder of iron metabolism within the body that may lead to fertility problems. Roughly 80% of men with hemochromatosis experience testicular dysfunction. Such dysfunction may be caused by abnormal iron deposition within the testes, liver, pituitary gland and other organs.

Other hormonal disorders

High blood levels of estrogen may be caused by a number of factors, including obesity, tumors of the adrenal cortex and testes (Sertoli cell tumors), and cirrhosis of the liver. Estrogen excess may lead to testicular failure because of inhibited pituitary gonadotropin secretion. Similarly, androgen excess - caused by adrenal cortical or testicular tumors, congenital adrenal hyperplasia (CAH), or misuse of anabolic steroids - may lead to secondary testicular failure and infertility.

High blood levels of glucocorticoids (corticosteroids involved in carbohydrate, fat and protein metabolism) - whether due to medication (to treat asthma, rheumatoid arthritis or ulcerative colitis) or systemic illness (e.g., Cushing's syndrome) - may result in testosterone suppression and reduced sperm production. For example, a high blood level of cortisol (adrenal steroid compound) will inhibit luteinizing hormone (LH) secretion and cause testicular dysfunction.

Excessive or below-normal activity of the thyroid gland - hyperthyroidism or hypothyroidism - alters sperm production. Hyperthyroidism speeds up the conversion of androgens to estrogens, producing testicular failure and/or erectile dysfunction. Hypothyroidism may increase the brain's production of thyroid-stimulating hormone (TSH), which, in turn, may spur excessive prolactin production and cause reduced potency and low sperm production.

Genetic Disorders

Male infertility can be a consequence of a genetic disorder. In such cases, defective genes may result in abnormal testes, abnormal sperm production and hormonal malfunction. Infertility is generally irreversible, and sex hormone therapy is necessary to ensure normal sexual function and masculinization in affected men.

Primary Hypogonadism - delayed sexual maturity due to abnormalities within the gonads themselves - is a defining characteristic of many genetic disorders associated with male infertility. Men with primary hypogonadism usually have severe, irreversible testicular defects because of genetic abnormalities.

Klinefelter's syndrome

Perhaps the best known of the genetic disorders that cause infertility in men. It is found in roughly 1 out of every 500 live births and often is not diagnosed before puberty. Patients with this condition have an extra "X" chromosome, one of the two sex chromosomes in humans. Normal women have two X chromosomes (XX), whereas normal men have an X chromosome and a Y chromosome (XY). This produces the genetic signature "XXY" and represents a total of 47 chromosomes within each bodily cell (the usual number is 46). Klinefelter's syndrome causes testicular failure due to sclerosis (hardening) of the seminiferous tubules within the testes (see also Anatomy & Physiology). ). In some individuals with Klinefelter's syndrome, genetic patterns variant (karyotypes) such as "XXYY," "XXXY," or "XXXXY" have been detected. Skeletal abnormalities are more common among men with multiple X chromosomes. Patients with chromosomal "mosaics" (XXY/XY) have a less severe form of Klinefelter's syndrome and may be fertile, since a normal ("XY") group of sperm-producing seminiferous tubules may exist within the testes.

Klinefelter's syndrome typically results in sterility. Although sexual function may be normal, sperm are not produced to father children. In adolescent boys, Klinefelter's syndrome may create distinguishing physical features, such as small firm testes, gynecomastia (overdevelopment of the male breasts), slowed growth of facial hair, and incomplete masculine body build. Most young men with Klinefelter's syndrome are tall (the average height is approximately 6 feet), yet they may not be coordinated or athletic. Psychological, social and learning problems are common in this group, as is mental retardation. Other associated conditions include glucose intolerance (inability to metabolize the sugar glucose) and varicose veins in the legs.

High levels of gonadotropins are usually found in the blood, and semen samples show azoospermia (lack of sperm). Also noteworthy is the imbalance in blood levels of estradiol (a form of the female sex hormone estrogen) versus androgen (male sex hormone). Although most adult men with Klinefelter's syndrome have normal sexual function (with adequate erection and ejaculation), some may be impotent and/or have a low sex drive, and they may exhibit incomplete development of the scrotum or penis.

Sex hormone therapy may be very beneficial for prepubescent boys with Klinefelter's syndrome, especially if their blood testosterone levels are low. Specialists generally recommend hormone therapy to ensure optimal sexual development in such cases - including growth of pubic and facial hair, increased size of the penis and scrotum, deepening of the voice, and increased muscular size and strength. This includes use of synthetic testosterone (male sex hormone) in the form of intramuscular injections, oral or buccal (through-the-gum) preparations, or transdermal (skin) patches. This treatment, however, does not repair the sperm production problems.

XX Disorder

Otherwise known as sex reversal syndrome -- a variant form of Klinefelter's syndrome. Although affected men have a normal number of chromosomes (46), the sex chromosome signature is "XX," with a displacement of the Y chromosome somewhere within the other pairs of somatic (bodily) genes. The signs of XX disorder are comparable to those of Klinefelter's syndrome, yet most individuals are short in stature are less likely to be mentally deficient, and may exhibit hypospadias (underside opening of the urethra in the glands penis).

XYY Syndrome

XYY syndrome has more a variable physical expression than other genetic abnormalities. Indeed, no consistent syndrome has yet been defined, since XYY men may suffer from abnormalities like seminiferous tubule sclerosis, or they may present with normal gonads. In general, though, men with XYY syndrome are extremely tall, and they may suffer from a pustular form of acne. Some individuals express antisocial behavior. Ejaculate samples from XYY men vary between azoospermia (no sperm) and normal sperm counts. Blood and urinary levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) often are normal; abnormalities in these hormone levels are related to the extent of germ cell damage within the testes.

Mixed Gonadal Dysgenesis

An inherited disorder with a distinctive genetic signature (45, XO/46, XY). It is defined by the presence of a testis on one side and a "streak" (primitive) gonad on the other side. The mixed character of this disorder is illustrated by the fact that some patients have external genitalia that appear female (although ovaries are not present internally), whereas others appear like normal men with one-sided cryptorchidism. If a patient with mixed gonadal dysgenesis has been reared as a male and has a normally descended testicle, then he may be fertile.

There is a high probability of malignant (cancerous) transformation in the tissues of the undescended testis and/or streak gonad among adults with this disorder. Nonmetastasizing (nonspreading) gonadoblastomas are the most frequently occurring tumors, but germinal cell tumors - which do metastasize - may occur along with them. Thus, most physicians recommend early removal of the gonads (except scrotal testes).

Noonan Syndrome (male Turner's syndrome)

Noonan syndrome is the male expression of Turner's syndrome, which is characterized by the genotype "XO." Men with Noonan syndrome usually are infertile due to cryptorchidism and insufficient sperm production. Like women with Turner's syndrome, men with Noonan syndrome have many distinctive physical features, such as short stature, low-set ears, webbed neck, upper eyelid droop (ptosis), and elbow deformity (cubitus valgus). Cardiovascular abnormalities also may be present.

Because of the testicular malfunction in these individuals, Noonan syndrome patients usually have increased blood levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (see also Normal Process of Sperm Development) Thus, hormone therapy may help to relieve their androgen (male sex hormone) deficiencies and crytorchidism, although their impaired sperm production is untreatable.

Myotonic dystrophy

An inherited disorder that is characterized by delayed muscle relaxation after initial contraction. Individuals with the disorder usually have physical features such as frontal baldness and opaque regions within the lens of the eyes. Gynecomastia (overdevelopment of the male breasts) does not occur.

Although puberty may be normal in affected men, myotonic dystrophy causes testicular atrophy (shrinkage) in a large percentage of adults (up to 80%). Such atrophy is attributed to abnormalities of the seminiferous tubules. Blood levels of follicle-stimulating hormone (FSH) are usually increased in proportion to the degree of testicular atrophy.

Although some spermatogenesis (sperm production) may be present, testicular biopsy usually shows disorganization of the sperm maturation process, with breakdown of primitive germ cells that ultimately become sperm and sperm-nourishing Sertoli cells of the seminiferous tubules, and eventual tubular sclerosis (hardening) (see also Normal Process of Sperm Development).

Because testosterone levels are normal in most men with myotonic dystrophy, no androgen (male sex hormone) therapy is necessary. Unfortunately, there is no treatment for infertility due to testicular damage in myotonic dystrophy patients.

5-alpha-reductase Deficiency

A familial disorder that falls under the banner of "pseudohermaphroditism" - that is, the gonads are of one sex, whereas the overall physical characteristics are of the opposite sex (in male cases, the individual is a genetic and gonadal male, with unfinished masculinization). 5-alpha-reductase is an important enzyme in the pathway of androgen (male sex hormone) activity. 5-alpha-reductase deficiency is typified by external female features at birth, accompanied by the presence of well-developed testes and scrotal structures (epididymis, vas deferens, seminal vesicles, ejaculatory duct, etc.

Individuals with 5-alpha-reductase deficiency often are raised as girls; however, at puberty, they may develop a penis and experience masculinization (beard growth, etc.). People with this disorder have a slightly increased blood level of luteinizing hormone (LH) and a normal or increased level of testosterone. Since the external genitalia may not be completely developed in affected individuals, those who are raised as men should undergo surgical repair of any defects such as cryptorchidism (the failure of one or both testes to descend into the scrotum) or hypospadias (underside opening of the urethra in the glands penis).

Androgen receptor Deficiency

Like 5-alpha-reductase deficiency, androgen receptor deficiency is a genetically-linked expression of abnormal androgen (male sex hormone) activity. And, like 5-alpha-reductase deficiency, androgen receptor deficiency can produce a syndrome of pseudohermaphroditism (see also 5-alpha-reductase deficiency). The clinical features of androgen receptor deficiency, also known as Reifenstein syndrome, may range from infertility alone to pseudohermaphroditism (incomplete masculinization of the external male genitalia in men with bilateral testes). Cryptorchidism may be present, along with vas deferens defects and incomplete sperm production.

Patients often show high blood levels of testosterone, coupled with increased levels of luteinizing hormone (LH) and increased secretion of estradiol (natural estrogen) by the testes. The enhanced estradiol output leads to feminization (development of female sex characteristics), androgen resistance and changeable degrees of masculinization. Irreversible fertility often results from the severe deficiency or lack of sperm caused by this disorder.

Sickle Cell Anemia - An inherited blood disorder caused by an abnormal form of hemoglobin - the oxygen-carrying molecule of the red blood cells. Men with sickle cell anemia often show evidence of hypogonadism (delayed sexual maturity), as well as slowed skeletal growth, small testes and low sperm density. Hypogonadism usually is related to testicular malfunction as well as hormonal imbalances (e.g., pituitary hormone and hypothalamic hormone irregularities). Blood testosterone generally is low in men with sickle cell disease, although luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels are variable and may be normal, low or even increased.

Cystic Fibrosis - Low ejaculate volume and azoospermia (lack of sperm in the semen) are common findings among men who carry a gene for cystic fibrosis. This is because male cystic fibrosis patients usually have an inherited, bilateral absence of the vas deferens and malformations or absence of seminal vesicles.

Other Genetic Disorders

Other genetic disorders reportedly may cause infertility:

· b-thalassemia, the reduced manufacture of "beta chain" portions of the hemoglobin molecule within red blood cells; symptoms of b-thalassemia are anemia, enlarged spleen, skeletal deformities and enlarged heart).

· Prune belly syndrome, a disorder typified by genitourinary abnormalities; in some individuals, early puberty may occur due to increased levels of testosterone, luteinizing hormone (LH]) and prolactin.

· Bladder exstrophy, the absence of part of the lower abdominal wall and frontal wall of the bladder.

· Epispadias, the absence of the upper wall of the urethra, which may open anywhere on the back of the penis, causing irregular ejaculation

· Myelodysplasia, the defective development of a part of the spinal cord.

Risk Factors Associated with Male Infertility

Fertility is a general indicator of a man's overall health. With the exception of inherited or other causes of irreversible damage to the sperm-making organs, a healthy lifestyle usually will result in the production of healthy sperm. Yet a number of harmful products, events, and behaviors may lessen male fertility. These factors range from common substances - such as tobacco and alcohol - to environmental toxins, such as lead and pesticides.

Nicotine

Nicotine, as absorbed through cigarette smoke or other tobacco products, is associated with low fertility, although the exact role played by this substance is not well established. Since many male smokers display significant reductions in sperm count and motility and increases in abnormal sperm morphology (shape), experts recommend quitting to enhance reproductive potential. In addition, recent findings suggest that miscarriage is significantly increased when both partners - or even just the male partner - smoke.

Alcohol

Alcohol use, especially when excessive, can injure the male reproductive system, cause impotence and decrease a man's capacity to produce healthy sperm. If chronic alcohol abuse leads to liver damage, an increase in estrogen (female sex hormone) may occur. In such a case, the man's female hormone level may be inordinately high, resulting in a low sex drive and reduced sexual performance.

Severe alcoholism can cause severe testicular shrinkage, failure of the Leydig cells (testosterone-producing cells of the testes), and impaired synthesis of testosterone. Affected men also may experience a loss of facial and pubic hair, shrinkage of the prostate, and gynecomastia (overdevelopment of the male breasts).

Marijuana

Research suggests that long-term use of marijuana lowers the sperm count, interferes with sperm motility, and causes sperm to develop abnormally. In addition, some findings suggest that marihuana may reduce blood testosterone levels. Marijuana use, like alcohol use, has been associated with the development of gynecomastia.

Opiates

Opiates, such as heroin and morphine, and related drugs, such as methadone, have been associated with the inhibition of gonadotropin (gonad-stimulating hormones) secretion and with reduced blood levels of testosterone (male sex hormone).

Anabolic Steroids

The use of anabolic steroids (synthetic derivatives of the male sex hormone testosterone) - for example, by athletes who try to enhance physical performance - has been linked to testicular shrinkage and depressed gonadotropin secretion. These effects may be temporary, but also may lead to permanent infertility.

Prescription Medications

Many prescription medicines can harm sperm or otherwise impair sperm production or quality. In addition, some medications can cause impotence (erectile dysfunction). Therefore, men who are trying to conceive a child with their partners should check with their doctors before using any prescription drugs. Medications of particular concern include:

· Amebicides (amoeba-killing agents)

· Anti-alcoholism drugs, such as tetraethylthiuram disulfide (Antabuse)

· Antibiotics, such as nitrofurantoins - which lower sperm production, macrolides (e.g., erythromycin - which impairs sperm function), tetracycline - which lowers the testosterone level, gentamicin - which impairs sperm function, and sulfa drugs

· Antidepressants, such as tricyclic drugs and monoamine oxidase

· inhibitors, which can cause impotence and problems ejaculating

· Antidiarrheal drugs, such as sulfasalazine, which decreases sperm motility and density

· Anti-edema drugs, such as spironolactone, which inhibits androgen production

· Antifungal drugs, such as ketoconazole, which inhibits androgen production

· Antihypertensive drugs, which can cause erectile dysfunction

· Anti-infective agents, such as hexachlorophene or amphotericin B

· Antiparasitic drugs, such as quinine or chloroquine

· Anti-ulcer drugs, such as cimetidine, which inhibits androgen production

· Androgenic steroids (see also Anabolic Steroids)

· Diuretics, "water pills," such as Aldactone or thiazides

· Gouty-arthritis drugs, such as colchicine and allopurinol

· Histamine receptor blockers

· Immunosuppressive agents, such as cyclosporine

· Oral hypoglycemia (low blood sugar) drugs, such as chlorpropamide

· Xanthines, used in medications for headache and allergy, such as caffeine or theobromine

DES (DES)

During the 1950s, many pregnant women took the drug diethylstilbestrol (DES), a synthetic estrogen, to prevent miscarriage. Men who were exposed in utero (within the womb) to this drug may experience abnormalities of the testes (atrophy, undescended testes) or epididymis (cysts, obstruction), along with reduced sperm production.

Chemotherapy

Although chemotherapeutic agents are constantly being improved and can successfully treat a wide variety of cancers, such agents pose many fertility concerns. Chemotherapeutic drugs often exert prolonged, toxic effects upon gonadal function. The drugs may cause direct damage to the primitive, sperm-forming germ cells of the testicular tissue (see also Normal Process of Sperm Development). In addition, hormonal function of the testes may be impaired.

Germ cell toxicity is especially noticeable following treatment with chemotherapeutic drugs known as alkylating agents. Some common alkylating agents are nitrogen mustards (chlorambucil, cyclophosphamide), nitrosoureas (CCNU, BCNU, MNU), methanesulfonic acid compounds (MMS, EMS, busulfan), ethylenimines (TEM, TEPA), and hydrazines (procarbazine). Other chemotherapeutic drugs that possibly may cause germ cell toxicity include doxorubicin, vinca alkaloids (vinblastine, vincristine), antimetabolites (cytosine arabinoside, methotrexate), antitumor antibiotics and cis-Platin.

Since many modern chemotherapeutic strategies use combinations of drugs, the risk of toxicity may be even greater. For example, multi-agent regimens such as "MOPP" (nitrogen mustard, vincristine, procarbazine, and prednisone) cause permanent sterility in a majority (approximately 90%) of male patients so treated for Hodgkin's disease.

Age-dependent effects are common to many chemotherapeutic drugs. So the task of treating children with cancer is complex. Before puberty, the germ cell tissues of the testes appear to be more resistant to modest doses of chemotherapeutic drugs than they are in adult testes. Yet during adolescence, severe germ cell toxicity may occur following the same drug doses. For example, researchers have observed toxic effects such as germ cell aplasia (no development of sperm-producing tissue), azoospermia (lack of sperm in the semen), elevated blood gonadotropins (gonad-stimulating hormones), reduced testosterone (male sex hormone), and gynecomastia (overdevelopment of the male breasts) among adolescent boys who received MOPP chemotherapy for Hodgkin's disease. By contrast, prepubertal boys showed no testicular injury, no changes in blood gonadotropins or testosterone, and no gynecomastia.

Semen cryopreservation - the sampling and freezing of semen - may offer an alternative to infertility among adolescent boys and men who must receive toxic chemotherapy. Semen cryopreservation may be used in combination with artificial insemination or in vitro fertilization techniques to conceive children (see also Artificial Insemination and In Vitro Fertilization). However, it should be mentioned that some cancer patients have underlying defects in sperm production prior to chemotherapy. Semen from such individuals may be of poor quality and unsuitable for cryopreservation.

Toxins in the Workplace

Occupational exposure to workplace hazards may damage the sperm-producing testicular germ cells and lead to infertility.

Lead, for example, has been found to interfere with the hypothalamic-pituitary-gonadal axis - the hormonal "feedback mechanism" of the reproductive system (see also Endocrine Disorders). Excessive lead exposure can cause suppression of blood testosterone level. Men with lead poisoning (e.g., battery plant workers) also may exhibit direct testicular damage in the form of fibrosis (fibrous tissue production) around the tubules, cavity formation, and decreased sperm production. Chelation therapy (therapy for metal poisoning) with EDTA (ethylenediaminetetraacetic acid) or BAL (2,3 dimercaprol:British anti-lewisite) may be helpful for the systemic effects of lead toxicity, although reproductive benefits have yet to be documented.

Dibromochloropropane (DBCP) - an agricultural soil fumigant - is associated with severe testicular toxicity. Men who have been exposed to DBCP frequently will suffer from small, soft testes, elevated blood gonadotropin levels, low testosterone levels, and few or no sperm in their semen. The reduction in sperm production is dependent upon the length and degree of DBCP exposure. In some cases, sperm production and fertility can be restored if the patient remains free from any contact with DBCP.

Radiation

The sperm-forming germ cells of the testis are very sensitive to radiation, probably due to their high rate of cell division (see also Normal Process of Sperm Development). Radiation-associated injury and reparability of germ cell tissue is dose-dependent. Germ cell damage is reversible at single exposures below 600 RDAs; however, above 600 rads, permanent infertility is likely. After exposure to 200 to 300 rads - the radiotherapy protocol for Hodgkin's disease patients - it may take up to 3 years for sperm production to fully recover; at 400 to 600 rad, the recovery time is roughly 5 years.

Thus, to preserve fertility, every effort should be made to guard the testes from radiation when radiotherapy is applied to the pelvis and other abdominal sites. The problem of "radiation scatter" is particularly important if there is less than 30 cm distance between the testes and the edge of the radiation field. In such cases, use of a testicular shield can minimize radiation exposure by three- to ten-fold.

Hyperthermia

Most fertility specialists believe that men should avoid all situations that may lead to hyperthermia - increased body temperature - in the scrotal region. In many cases, infertile semen may be caused by an intrinsic failure of heat regulation in the testis, leading to high temperatures that impair sperm production. For this reason, doctors endorse the repair of significant varicocele (enlarged, "varicose" vein in the scrotum), which can result in increased scrotal temperature (see also Surgical Management of Infertility). Physicians also recommend against exposure to high heat through saunas and hot tubs. In addition, it is suggested that men stop wearing tight-fitting briefs or bikinis in favor of boxer shorts.

Hypothermia devices - which are used to lower testicular temperatures -sometimes restore sperm quality in infertile men with high scrotal temperatures, but are rarely used.

Sexual Dysfunction

Problem with sexual performance is an important risk factor for infertility, and sexual dysfunction is often correctable. Unfortunately, though, sexual dysfunction is a factor that may not be recognized or emphasized by patients who present infertility problems to their physicians. Sexual dysfunction includes such disorders as impotence (erectile dysfunction), low libido (sexual desire), poor timing of sexual intercourse, failure to complete intercourse, and ejaculation abnormalities.

Erectile dysfunction often occurs because of emotional factors such as depression, anxiety about sexual performance, or fear of pregnancy and fatherhood. Other, unsuspected factors - such as medication use - also may cause erectile dysfunction (see also Prescription Medicine). Affected men may be unable to achieve or maintain an erection until ejaculation has occurred, even though their testicular function is normal. If testicular function is not normal, men may experience a loss of libido or potency. In addition, the psychological impact of an abnormal sperm test (low sperm count, irregular sperm, etc.) may, in itself, cause sexual performance problems in both the man and his female partner. Counseling and stress-reduction techniques often are helpful in alleviating sexual dysfunction due to emotional factors. Or, if the dysfunction is caused by medication, a simple change in the class of drug prescribed may solve the problem.

Some couples may not understand the proper timing of sexual intercourse. Since ovulation occurs mid-cycle in most women, any avoidance of intercourse during this period - whether because of religious considerations (e.g., Orthodox Jewish couples abstain from sexual relations until 1 week after the last menstrual period) or physical complaints (some couples refrain from sex if the woman complains of "mittelschmerz," abdominal pain related to ovulation) - may result in infertility. Thus, the timing of intercourse to coincide with the woman's ovulation cycle will enable many such couples to conceive a child.

Ejaculation disorders also can reduce a man's potency. For example, even though vaginal penetration may be normal, semen may not be deposited directly within the vagina if the man has problems with premature (too early), retrograde or incomplete ejaculation. Similarly, semen may not be released directly within the vagina if the man has an irregular penis - for example, with an underside opening of the urethra (hypospadias), too-tight foreskin over the glands (phimosis) or downward curvature (chordee) (see also Anatomy & Physiology and Retrograde Ejaculation). On rare occasions, an intact hymen (membrane over the vaginal opening) will prevent the penis from entering and ejaculating into the vagina. Ejaculation disorders often are treatable (see also Retrograde Ejaculation), as are penile abnormalities, which can be corrected by surgical techniques.

Other, less researched factors - such as psychological stress and disturbance of the sleep cycle - also may contribute to sexual dysfunction and infertility.

What are the treatments?

Recently, much research has been conducted to determine the causes of male infertility and to expand the range of treatment options. Some of the currently available strategies involve drug therapy, neurologic evaluation, surgery and Assisted Reproductive Technologies (ART). ART utilizes many techniques, including artificial insemination, in vitro fertilization (IVF) and sperm microinjection methods (see also Surgical Therapy).

NEUROLOGIC EVALUATION

Neurologic (nervous system) evaluation is essential in men who are infertile because of impotence, spinal cord injury, other injury involving the nervous system (for example, surgical damage of the nerves that supply the penis), or suspected neurologic disease. To assess risk factors for neurologic disease, the physician first will take a careful medical history. This will help to identify related disorders such as hypertension (high blood pressure), diabetes, cardiovascular disease, and bowel or bladder disease.

Next, tests for neurologic deficit (reduced nerve activity) will be performed. Deep tendon reflexes will be measured in the lower limbs. In addition, the physician may want to measure "evoked responses" - electrically stimulated responses that indicate the function of the nerve pathways. The sacral evoked response, also known as sacral latency, measures the bulbocavernosus (penis muscle) reflex. The penile skin is electrically stimulated, and an electrode measures the time from stimulation to response of the bulbocavernosus (normally about 40 msec). Electroencephalographic (EEG) leads on the scalp also may be used to measure genitocerebral evoked response - the time between penile stimulation and cerebral (brain) processing of the stimulus.

If there is still doubt about a man's neurologic status, the physician may perform the nocturnal penile tumescence test (NPT). A strain gauge device is used to measure normal tumescence (swelling) and rigidity of the individual's penis during sleep. In general, vascular (blood vessel-related) impotence is unlikely if there is normal tumescence and rigidity during sleep. The NPT is particularly helpful to physicians who are trying to distinguish psychological from nonpsychological causes of erectile dysfunction.

DRUG THERAPY

Drug therapy for male infertility includes substances designed to improve sperm production such as Testosterone patches (Testoderm), hormone supplements for endocrine system disorders, antibiotics, such as Levaquin for fertility-impairing infections and immunologic agents, among other medications.

Testosterone

Testosterone, an androgenic (male) sex hormone required for sperm manufacture, has been employed as a form of "rebound" therapy in men who suffer from inadequate sperm production. In brief, testosterone - in the form of 200 mg testosterone cypionate or enanthate, administered by weekly intramuscular injection for up to 12 weeks - is used to stop sperm production and cause azoospermia (no sperm in the semen). When testosterone is discontinued, sperm production may recover, or "rebound," and lead to significantly increased sperm counts in a proportion of patients. Such rebound usually occurs 4 to 6 months after stopping testosterone treatment. Unfortunately, success rates from this therapy are poor, and some men run the risk of permanent azoospermia after treatment.

Clomiphene Citrate

Clomiphene citrate, a synthetic steroid drug related to estrogen (female sex hormone), has both anti-estrogenic and estrogenic effects. In men with oligospermia (low sperm count), clomiphene has been used to increase gonadotropin secretion, which, in turn, may stimulate testosterone release and improve sperm output (see also Endocrine Disorders). Yet the male response to the drug is not as pronounced as that seen in women. Clomiphene usually is given in oral daily doses of 25-50 mg for a 3- to 6-month period. However, the results from clomiphene trials are extremely variable, with differing success rates for conception. Therefore, more clinical data are needed to confirm the effectiveness of this drug.

Tamoxifen

Tamoxifen, like clomiphene citrate, is an oral anti-estrogen compound that has been used to treat male infertility. But, unlike clomiphene, tamoxifen has no estrogenic activity. Tamoxifen stimulates sperm output by increasing the release of gonadotropins. In current studies, the most common oral dosage is 20 mg daily. As with clomiphene, some men respond favorably to tamoxifen and show improved semen quality and increased rates of conception; however, there are still questions regarding which patient groups are most likely to be helped by tamoxifen therapy. Recent findings suggest that pregnancy may occur in up to one-third of couples in whom the male partner has received tamoxifen therapy.

Gonadotropins

Gonadotropins are gonad-stimulating hormones. The gonadotropins human chorionic gonadotropin (HCG), human menopausal gonadotropin (HMG), and their combinations very successfully treat men with hypogonadotropic hypogonadism (delayed sexual maturity due to sex hormone deficiency) (see also Hypogonadotropic Hypogonadism). Both HCG and HMG stimulate testosterone synthesis, which, in turn, improves sperm production and pregnancy rates.

Gonadotropin therapy also has been tested in men with oligospermia (low sperm count) due to unknown causes. For these men, HCG and/or HMG therapy may or may not improve fertility. Given the expense of such therapy and potential difficulty of administration (HMG requires injection), most specialists do not recommend gonadotropin therapy for oligospermic patients.

Antibiotics

Antibiotics frequently are prescribed to eliminate infections that could impair fertility, such as infections of the urinary tract and prostate. The physician will be especially inclined to prescribe an antibiotic if leukocytes (white blood cells) are detected in the man's semen sample. Strong antibiotic medications - like double- strength trimethoprim plus sulfamethoxazole (Bactrim DS) and doxycycline hyclate (Vibramycin) - often are the drugs of choice. They usually are administered for intervals of 1 to 3 months. Nitrofuran antibiotics are avoided, since they may impair sperm maturation. STDs, such as gonorrhea or ureaplasma, commonly are treated with ceftriaxone sodium or doxycycline.

Methylprednisolone

Methylprednisolone is a corticosteroid medication that has been prescribed as a treatment for immunologic infertility. In particular, methylprednisolone is used to suppress blood levels of antisperm antibodies. In men, the drug is given a specific number of days before the female partner's time of ovulation (fertile period).

Methylprednisolone therapy is very controversial, since, with the high doses required (96 mg daily), it can produce many side effects that are associated with other forms of steroid therapy - that is, worsened peptic ulcer disease, skin disorders, glucose intolerance (inability to metabolize the sugar glucose) and mental disorders. Success rates are varied, but very few studies have shown much benefit.

Bromocriptine

Bromocriptine is a drug that is classified as a dopamine agonist. This means that bromocriptine acts like dopamine, a catecholamine (sympathetic nervous system chemical) that stops the release of prolactin hormone from the pituitary gland. Bromocriptine therapy is useful for men in whom impaired sperm production is due to hyperprolactinemia (high blood level of prolactin).The customary daily dose of bromocriptine is 5-10 mg. The side effects of bromocriptine therapy include high blood pressure, headache, dizziness, nausea, and vomiting.

SURGICAL THERAPY

Surgery is appropriate for the treatment of male infertility due to genital tract obstruction, varicocele (enlarged, "varicose" vein in the scrotum), or previous vasectomy.

Vasoepididymostomy

Vasoepididymostomy is a microsurgical procedure that uses a microscopic camera and very small operative tools to correct obstructions in the genital tract (see also Vasography). The procedure requires removal of the blockage in the epididymis (the coiled tube that extends the length of each testis and connects with a larger duct - the vas deferens) and re-attachment of the epididymis to the vas deferens. Vasoepididymostomy may improve pregnancy rates by up to one-third of all patients; however, the success of vasoepididymostomy is dependent upon the experience and technical expertise of the microsurgeon.

Classic signs of epididymal "blockage" are a swollen top of the epididymis, the presence of sperm in semen drawn from the obstructed segment, and otherwise normal testes. Blockages frequently arise in the epididymis because of inflammation due to sexually transmitted diseases (STDs). Gonorrhea is an STD that, if left untreated, is likely to damage the epididymis and produce obstruction. Other, rarer causes of obstruction include cysts, inherited atresia (tubal closure), and genital tuberculosis. Vasectomy (a contraceptive procedure involving surgical removal of a portion of the vas deferens) currently is the leading cause of infertility secondary to genital tract obstruction (see also Vasovasostomy). There is an increased likelihood of epididymal blockage among men who have had vasectomies of more than 10 years' duration.

Varicocelectomy

Varicocelectomy - the cutting away of a varicocele - is usually performed with regional or general anesthesia. The surgeon makes an incision into the groin, and the problematic venous system then is repaired. The venous channels are divided to prevent varicocele recurrence, and the external cremasteric vessels (the veins associated with the testis-elevating muscle) also are tied off and divided. Varicocele repair often dramatically increases semen quality and pregnancy rates in infertile couples. The major complications of varicocelectomy are varicocele recurrence and formation of hydrocele (collection of fluid in a contained area). However, newer microsurgical techniques have substantially limited these complications.

Varicocele Embolization

Varicocele embolization is an alternative to surgery for men with varicocele. Embolization is an outpatient procedure in which the varicocele is closed off (occluded) by means of a balloon catheter (flexible tube with a tiny detachable balloon), steel coil, and/or sclerosing (vessel-hardening) solution.

First, the patient is catheterized (a flexible tube is inserted into a blood vessel) at a few venous sites (e.g., right femoral vein, left renal vein, left internal spermatic vein). The patient then performs a Valsalva maneuver (a forced "exhale" with a closed nose and mouth) and undergoes venography (X-ray of a vein filled with contrast medium) to identify the location of the varicocele. Next, the balloon catheter is drawn through the vessel and usually is inflated at the level of the pubic ramus (e.g., pubic branch of the internal spermatic vein), below the insertion of most collateral (parallel) veins. Careful attention is paid to the level of occlusion to avoid varicocele recurrence. If follow-up venography shows that residual collateral veins remain, further occlusion may be performed by using a steel coil or another balloon with or without a sclerosing agent such as glucose. After the catheter materials are withdrawn and no venous bleeding is observed, the patient is sent home to resume normal activities the next day.

Since venography is used to visualize and "target" the veins during embolization, varicocele theoretically should not recur in most men, but there is still a high rate of technical failure and/or recurrence. On very rare occasions, balloons have moved from the scrotal venous system into the general circulation and caused embolism (clots) in the lung and other sites.

Vasovasostomy

Vasovasostomy, otherwise known as vasectomy reversal, is the re-connection of the severed ends of the vas deferens. This procedure, like vasoepididymostomy, commonly is conducted using microsurgical methods. However, nonmicroscopic, "macrosurgical" techniques also are successfully employed. Most vasectomy reversal procedures are conducted on an outpatient basis.

During microsurgical vasovasostomy, most surgeons use a "two-layer" technique in which both the inside and outside layers of the severed tubules are reconnected with tiny sutures. Close attention is paid to the character of the fluid that is obtained from the testicular end of the vas: if the fluid is clear and colorless and if sperm are present, the results of vasovasostomy usually are favorable. By contrast, if the fluid is thick or creamy and if sperm are absent, a vasoepididymostomy usually is performed rather than a vasovasostomy (see also Vasoepididymostomy).

The complications experienced after vasovasostomy are infrequent and minor. After vasovasostomy some men are found to produce antisperm antibodies - immune system molecules that lessen the fertilizing potential of sperm. The antibody production is a result of the vasectomy. Some physicians recommend the collection and freezing of sperm from the site of vasectomy reversal in the event that sperm are abnormal or sperm output is inadequate after successful reconnection of the vas.

The new forms of fertility treatment - collectively known as Assisted Reproductive Technologies (ART) - incorporate many methods of sperm retrieval and preparation. Once the sperm have been processed to ensure optimal fertilizing potential, they are used in a variety of procedures that aid the process of conception. These procedures include artificial insemination (AI), in vitro fertilization (IVF), and sperm microinjection techniques.

Sperm Retrieval

Sperm retrieval is not limited to ejaculated semen. With today's technology, sperm can be obtained from men with azoospermia (lack of sperm) that is caused by an obstructive lesion, failed vasectomy reversal, inherited absence of the vas deferens, or other uncorrectable blockage.

For example, applying microsurgical methods in a process known as micro epididymal sperm aspiration (MESA), sperm can be gathered close to the blocked portion of the epididymis, the elongated, coiled duct that provides for the maturation, storage, and passage of sperm from each testis. Similarly, percutaneous epididymal sperm aspiration (PESA) uses a small needle to penetrate the testicular skin and draw sperm from the area near the epididymal obstruction. Testicular sperm extraction (TESE), the removal of a small amount of testicular tissue under local anesthesia, also can be a source of sperm.

Sperm retrieval methods usually are scheduled to coincide with the female partner's time of ovulation, so that they may be used for in vitro fertilization (IVF) of a retrieved egg. Sperm that is retrieved by MESA, PESA or TESE then can be processed for use in procedures such as intracytoplasmic sperm injection (ICSI) (see also Intracytoplasmic Sperm Injection). While excess sperm from MESA or PESA usually can be frozen for future use, most TESE-derived sperm are not of sufficient quality or quantity for frozen storage (cryopreservation). Multiple MESA or PESA procedures are not recommended, since repeated surgery can lead to scarring around the site of incision.

Most patients are advised to wear scrotal supports for 1 week following MESA, PESA or TESE. Side effects are rare, although postoperative pain and swelling may persist for up to 2 weeks.

Sperm Washing

Sperm washing is a procedure that is used extensively for the treatment of semen with low sperm counts, abnormal sperm forms, antibodies, and other fertility-impairing features (see also Other Tests of Sperm Function). The "washing" is accomplished by adding culture medium (a fluid containing nutrients and buffers) to the semen and spinning the entire sample in a centrifuge (a machine that uses centrifugal force to separate heavier and lighter elements in a solution). The heavy sperm "pellet" is then rewashed in culture medium. If the physician needs a "rise" or "swim-up" fraction of the most active sperm, the concentrated sperm sample is incubated (kept warm) for about 1 hours, and the swimming sperm are extracted from the top of the test tube. If the physician wants to enhance the fertile potential of the sperm, TEST-yolk buffer (a special solution containing buffers, chicken egg yolk, glucose and antibiotics) may be used during the washing and pellet dilution procedures. The sperm that are gathered from such washing methods are subsequently used for artificial insemination and in vitro fertilization procedures.

Artificial Insemination

Artificial insemination (AI) is a process in which a relatively large number of healthy sperm are deposited in a woman by artificial means. The sperm are placed either at the entrance to the cervix or directly into the uterus (womb) near the fallopian tubes (intrauterine insemination or IUI). Artificial insemination is particularly useful when the male partner's sperm count is low or when sperm quality is below average (e.g., in cases of spinal cord injury, ejaculation disorder or impotence). The sperm can be prepared by washing, concentration, or other methods to ensure the best chance of conception (see also Sperm Retrieval). Artificial insemination also is commonly performed using sperm from a donor.

In Vitro Fertilization

In vitro fertilization (IVF) is, by definition, the fertilization of an egg in the laboratory. Using a variety of hormonal drugs, the woman's ovaries are "super stimulated" to produce eggs. Then, many mature eggs are gathered from the ovaries, and they are fertilized in the laboratory using the man's sperm. Two methods used to collect the eggs. Transvaginal aspiration is an ultrasound-guided technique in which the eggs are aspirated (drawn out) via the vagina; this procedure also is known as TV collection. Laparoscopy involves an incision through the abdomen to extract the eggs.

Once the eggs have been collected, they are placed in a special fluid and are incubated (kept warm) with a prepared sample of the man's semen. The semen sample will have been processed to separate out the most active, healthy sperm. After the eggs are fertilized (roughly 48 hours after collection), they are replaced inside the woman's uterus.

Intracytoplasmic Sperm Injection

Intracytoplasmic sperm injection (ICSI) is an IVF procedure in which a single healthy sperm is injected directly into the egg. ICSI is especially useful when the man's sperm count is very low or many sperm are abnormal or immotile (see also Sperm Retrieval). A tiny injection pipette is used to pass the sperm through the zona pellucida (outside layer) of the egg into its ooplasm (central substance). In general, ICSI is performed on several eggs. Once they have been fertilized, they are replaced inside the woman's uterus after a period of about 48 hours.

Gamete Intrafallopian Transfer

Gamete intrafallopian transfer (GIFT) is an ART procedure in which the egg and sperm (gametes) are placed together within the fallopian tubes. Like IVF, GIFT requires prior, hormone-induced "super stimulation" of the woman's ovaries to produce mature eggs. The eggs then are retrieved from the woman by laparotomy, a surgical incision through the abdomen. After a number of mature eggs have been collected, they are combined with sperm which, as in IVF, has been treated to concentrate the most healthy and active cells. Finally, the gametes are transferred back into the fallopian tubes, where fertilization should take place. Any embryos that result from this procedure will naturally descend into the uterus for implantation.

ELECTROEJACULATION

Electroejaculation - ejaculation that is stimulated by an electrode - is a successful form of therapy for men who have normal testes but who cannot emit semen or ejaculate because of a fault in the sympathetic nervous system. Candidates for electroejaculation include men who have undergone orchiectomy (testis removal), retroperitoneal lymph node dissection (RPLND) or spinal cord injury.

The technique of electroejaculation involves the placement of a probe in the rectum (end of the large intestine). Electrical current from the probe then causes the emission of semen due to direct stimulation of nerve fibers within the male reproductive tract. Forceful ejaculation generally does not occur during this procedure, and semen may be released in an antegrade/retrograde manner - that is, semen may dribble out through the urethra, or it may be released backward into the bladder (see also Retrograde Ejaculation). Because semen may need to be retrieved from the urine, the urine will be made alkaline (nonacidic) by having the patient take sodium bicarbonate tablets (600 mg) during the day before the procedure.