Anatomy & Physiology

The Testes

The testes, or testicles, are a pair of sperm-producing glands located in the scrotum, the sac holding the testes. The testes are also responsible for the secretion of the androgenic (male) hormone testosterone. In order for a man to be fertile, at least one testis and its corresponding tubular system must be able to manufacture and carry sperm.

The testes are made up of collagen-containing supportive tissue, a network of ducts known as the seminiferous tubules, and fatty Leydig (interstitial) cells that lie around and between the seminiferous tubules. Within each testis, the sperm are produced in the seminiferous tubules, the basement membranes of which contain primitive "germ" cells that eventually become sperm (see also the Normal Process of Sperm Development). The sperm then are conducted through the epididymis - a coiled tube that begins at the top of each testis and descends along its length. The epididymis is divided into regions known as the head, body and tail. The tail of the epididymis connects with a larger, muscular, excretory duct - the vas deferens - which continues upward for roughly 14 inches until it reaches the area behind the bladder. There, at the base of the prostate (a gland that surrounds the neck of the bladder and urethra and adds a secretion to semen), the ends of the vas deferens join with a pair of pouches called seminal vesicles. The seminal vesicles produce fluid to sustain the sperm. The united vas deferens and seminal vesicles become the ejaculatory ducts. Both ejaculatory ducts enter the prostate gland, where they direct the ejaculate - sperm-containing semen - into the urethra, the tube that extends from the bladder to the end of the penis and passes urine or semen out of the body.

The Penis

The penis has three distinct anatomic parts - the body, the glands and the root.

The body is the outer portion of the penis that is itself composed of three tube-shaped structures: the corpora cavernosa (two upper chambers holding the erection-forming tissue of the penis) and the corpus spongiosum (the spongy, lower chamber that surrounds and protects the urethra).

The corpora cavernosa and the corpus spongiosum are each enclosed within tough white coverings called the tunica albuginea. The fibers of the tunica albuginea form a porous wall that lets blood from one chamber enter the other chamber. In this way, the chambers act as a single unit. The corpora cavernosa split at their ends to form the crura - strong, fibrous tails that connect to the pubic bone and hip. The crura are surrounded by muscles that help them to contract during ejaculation.

The tip of the penis, or glands, is created by the progressive widening of the corpus spongiosum. At the end of the glands is the opening of the urethra.

The root is located within the forward-facing region of the pelvis. It is composed of the corpora chambers, which divide in two to form the crura. In front, the root is anchored to the pubic bone.

Most sensation within the penis is provided by the dorsal penile nerves, which is a branch of the internal pudendal nerves. The pudendal nerves also send signals to the muscles that control ejaculation - ejection of semen from the penis. Erection occurs due to the action of specific nerves known as the nervi erigentes.

Blood flow within the penis primarily is provided by the cavernous arteries, branches of the penile artery. The cavernous arteries lie in the middle of the corpora cavernosa chambers; they separate to form numerous spiral branches called helicine arteries. This network supplies blood to the erection-forming tissue of the penis. Blood leaves the penis by three major veins: (1) the deep dorsal vein, (2) the intermediate, cavernous and crural veins, and (3) the superficial dorsal vein. The deep dorsal vein drains most of the blood from the penile chambers (corpora cavernosa, corpus spongiosum) and from the glands penis.

The Urethra (ani)

In men, the urethra is a tube that extends from the bladder to the end of the penis. It passes urine or semen out of the body. The urethra is approximately 8 to 9 inches in length and extends from the bladder neck to the end of the penis. The male urethra is composed of three portions - the prostatic, membranous and spongy portions. The prostatic portion is the widest part of the tube, which travels through the prostate gland. Its walls are made up of fibrous tissue, muscle fibers, and tiny glandular openings that connect to the prostate. The ejaculatory ducts (video) of the prostate direct semen into the urethra. The membranous portion of the urethra is approximately three-quarters of an inch long and lies between the triangular ligaments of the male pelvis. The spongy portion is the longest part of the urethra, which extends through the body of the penis and exits at the glands. The urethra is surrounded and protected by the corpus spongiosum.

Normal Process of Sperm Development (ani)

The production of sperm, or spermatogenesis, is a complicated process of cell division. First, primitive germ cells known as spermatogonia divide to produce "offspring" cells, or spermatocytes, that ultimately redivide twice to form young sperm cells known as spermatids. The spermatids then mature and are transformed into spermatozoa, or sperm cells. Each spermatozoon has one half of its bearer's genetic material, and each contains mitochondria (energy-generating organelles) to power its tail during the journey to fertilize an egg.

Spermatogenesis usually occurs among groups of cells. Such groups, or generations of sperm, pass through the same developmental stages together. Within the ductal network of the seminiferous tubules (see also Anatomy & Physiology), six developmental stages make up one spermatogenesis cycle - each of which lasts approximately 16 days. Almost five (4.6) cycles are needed to produce a mature sperm from a "germ" spermatogonium cell. Thus, the entire sperm production process takes about 2 1/2 months (16 days x 4.6 cycles = 74 days, or 2 1/2 months). So, sperm that are mature now may have been affected by risk factors that were present 2 to 3 months ago.

The process of sperm formation is under endocrine (hormonal) control. Such endocrine control represents a delicate balance between the secretions of the testes, thyroid (two-lobed gland within the neck), adrenals (glands above each kidney), pituitary (gland at the base of the brain), and hypothalamus (pituitary-linked organ). Hormones that are specifically involved in spermatogenesis include:

• Testosterone - produced by the Leydig cells of the testes; needed for sperm manufacture.
• Follicle-stimulating hormone (FSH) - produced by the pituitary; targets Sertoli cells during spermatogenesis.
• Interstitial cell-stimulating hormone (ICSH) or luteinizing hormone (LH) - produced by the pituitary, regulated by Gn-RH. LH stimulates testosterone production.
• Gonadotropin-releasing hormone (Gn-RH) - produced by the hypothalamus.
• Prolactin - produced by the pituitary, increased prolactin may decrease Gn-RH, thereby lowering testosterone.

The spermatogonia (primitive germ cells) begin the developmental process within the lower regions of the seminiferous tubules. Here they are nourished by the tubules' Sertoli cells and protected from assault by the body's immune system (sperm are first made during puberty, long after the time of self-recognition by the immune system). As the sperm mature, they are stored in the upper compartment of the tubules. Spermatozoa increase in motility (movement) and fertile potential during their passage through the epididymis - a journey that takes roughly 4 days. The epididymis acts as a storage area for mature sperm, more than 50% of which may be located in the epididymis tail. From the epididymis tail, the sperm then enter the vas deferens, where they are pushed by muscular contractions into the ejaculatory duct (see also Anatomy).

Prior to ejaculation, fluids from the seminal vesicles and prostate are secreted into the rear of the urethra. The first portion of ejaculate contains a small amount of sperm-rich semen from the vas deferens and most of the prostatic secretions. The secretions provide elements that are essential to the seminal fluid: zinc, phospholipids (fatty compounds), spermine (an amine compound), and phosphatase (an enzyme). The second portion of ejaculate is much larger in volume and is provided by the seminal vesicles. It contains nourishment and other essential substances for the sperm, such as fructose (sugar); prostaglandins, fatty acid compounds that spur contractions in the muscles of the uterus and fallopian tubes and are believed to aid in the sperm's passage to the womb; buffers (neutralizers) for the acidic vaginal environment; coagulating (gelling) compounds; and additional prostatic secretions.

How is this condition diagnosed?

• Evaluation
• Medical History
• Reproductive History
• Other Factors
• History of Infertility
• Physical Examination
• Lab Tests
• What Does Semen Contain?
• Other Sperm Tests
• Other Tests

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 herniorrhapy, 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 secondarty 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 (see also What is Male Infertility?). Among these factors, physical variables that affect the structure of the testes are particularly important.

• Cryptorchidism
• Testicular Tumors
• Testicular Trauma
• Varicocele
• Sexually Transmitted Diseases
• Systemic Illness
• Duct Obstruction
• Retrograde Ejaculation
• Neurogenic Causes
• Endocrine Disorders
• Genetic Disorders

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 gonasotropin (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) (see also Medical Management of Infertility). 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) (see also Assisted Reproductive Technologies).

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.

• 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 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.