This conference was created with the expert advice and counsel of Dr. Anthony J. Thomas, Jr., Head, Section on Male Infertility, Glickman Urological Institute, Cleveland Clinic Foundation. Dr. Thomas is an expert in andrology, the subspecialty of urology dealing with male reproductive function. I would especially recommend Dr. Thomas's book, written for the lay public, Overcoming Male Infertility, published in 2000.
Suppose you are one of the 10-15% of couples in Western countries who want children but are experiencing problems with fertility. Where do you go for help? Just as there are many causes of infertility, there is a wide range of available remedies, from seeing your primary physician for a basic medical exam and information about the best timing of intercourse for conception to placing the entire reproductive process under the control of a specialist. When you do seek help, however, it can be helpful to have educated yourself about the current state of knowledge about infertility and infertility treatments. In this article, we will discuss male infertility, a problem that is far more common than many people realize.

By [any] measure, male infertility seems to be a significant factor in about 40% of couples who have infertility problems.

Statistically, 30-40% of fertility problems are caused by problems with the male, and 30-40% by problems with the female. The remainder either are caused by a combination of problems on both sides or are unknown. The Centers for Disease Control collects data from fertility clinics doing in vitro fertilization. Their latest figures on infertility causes in couples in which the woman is under 35 are: 40% female, 23% male, 17% combined male and female, 10% more than one female factor and 10% unexplained. By either measure, male infertility seems to be a significant factor in about 40% of couples who have infertility problems.

What Are Infertility, Subfertility, and Sterility?
Doctors use these and other terms to define different types of fertility-related conditions. Even so, the definitions of the above terms have changed as technology has advanced.

Sterility is the absolute inability to procreate. For instance, a woman has no uterus or a man has no testes (the male sex organs). In years past, a woman with blocked fallopian tubes or a man with an obstructed vas deferens would be considered sterile and beyond help. With the advent of assisted reproductive technology (ART), however, this is no longer the case. Many couples who were once in this category can now get help.

Infertility is usually defined as the inability to achieve pregnancy after one year of frequent, unprotected intercourse. This is not an exact measurement. Over time many couples in this category may, in fact, achieve pregnancy. Statisically, after five years, nearly one half of so-called "infertile" couples do conceive.

Subfertility is used to describe the gray area between normal fertility and sterility; the term is often used interchangeably with infertility.

Fecundability, from "fecunditas," the Latin word for fertility, is the average pregnancy rate after one menstrual cycle. The normal rate in humans is 20%. Seventy-five percent of normally fertile couples are expected to have conceived in six months, and almost 100% by one year.

Normal fertility can be considered from the point of view of the couple, the female, or the male. We are going to look at male fertility — its biological steps and mechanisms, defects, the causes of those defects and what can be done to remedy them.

Normal Male Fertility
As male factors have been increasingly implicated as a major cause of infertility, investigators have focused on the underlying physical processes in men. If the sperm count is low, then why? Or, if the sperm count is normal, why do the sperm not fertilize?

That there are literally dozens of factors leading to a completely normal spermatozoon, the form of sperm that is present in semen. These involve the structure of the testis; the hormones that influence its function; the receptors for these hormones; the maturation process through which the germ cell develops into a spermatozoon; the composition of the seminal plasma; and all the enzymes, receptors, and reactions that make the sperm capable of fertilizing the egg. In these steps, there are dozens of occasions for mistakes and problems. First, let us look at how male fertility works when it works correctly.

Role of the Pituitary
The testis, or testicle, has two main parts. What is called the interstitial portion contains the Leydig cells, which produce the male hormone testosterone and are sensitive to another hormone called luteinizing hormone (LH). The other component is the seminiferous tubules, which contain the Sertoli cells and the germ cells; these are influenced by follicle stimulating hormone (FSH) and testosterone. LH and FSH are secreted by the pituitary gland in response to gonadotropin releasing hormone (GnRH), which is a substance secreted from nerve cells in a part of the brain called the hypothalamus. GnRH goes directly to the pituitary gland in pulses which range from once an hour or 1-2 times in 24 hours. There is a negative feedback loop by which GnRH is "turned off" by testosterone. FSH is also turned off by inhibin, a substance which is secreted by the Sertoli cell.

It is important to remember that GnRH is secreted in pulses, because if it is introduced to the body in a steady dose, for example by taking the drug leuprolide acetate (Lupron® or Zoladex®), the pituitary will stop secreting LH and FSH, testosterone levels will decrease; and spermatogenesis, or the production of sperm, will stop. A second important point is that excessive testosterone — whether given for replacement, bodybuilding, or other purposes — can inhibit GnRH and sperm production.

Finally, the pituitary hormone prolactin (PL) can sensitize the LH receptors on the Leydig cells that produce testosterone. Prolactin also affects the function of both the prostate gland and the seminal vesicles. Elevated PL, which is often caused by a growth called a pituitary adenoma, can therefore interfere with GnRH function.

Testicular Function
Ninety percent of the volume of the testes is taken up by the seminiferous tubules, which is where sperm are generated. Germ stem cells, called spermatogonia, provide sperm cells throughout a man's life. Each spermatogonium ultimately produces four spermatozoa.

Each spermatogonium ultimately produces four spermatozoa.

As sperm cells develop, they go through several stages, from spermatogonia to spermatocytes, to spermatids, and finally to spermatozoa. As the spermatid matures, it is surrounded by a Sertoli cell, often called a "nurse" cell. Here the sperm develops its characteristic features — the head, the midpiece and the tail. The whole process from spermatogonium to spermatozoa, or sperm, takes about 74 days. As the sperm exit the seminiferous tubules, they have very little ability to move (motility), and cannot yet fertilize an egg on their own.

The spermatozoa then move to the epididymis, a long, tightly packed convoluted tubule that can be felt along the outside of the testis. As the sperm traverse the epididymis, further maturation takes place; this takes another 10-15 days. So from germ cell to active spermatozoon there is about a 90-day development period. That means that if spermatogenesis were to stop completely at the germ cell level, the actual effect on sperm count would not be seen for three months. Conversely, recovery and resumption of spematogenesis may not be detectable by measuring sperm count for three months or so.

Semen Production
The secretions containing sperm that exit the epididymis make up only about 10% of the total volume of the semen. These sperm are transported via a tube called the vas deferens. Each vas deferens joins the duct from the seminal vesicle to form the ejaculatory duct, which enters the urethra and crosses over the prostate gland.

The seminal vesicles contribute about 70% of the volume of semen. These consist of secretions that are alkaline and rich in fructose; they also contain coagulating factors. The prostate contributes another 20% of semen volume. Its secretions are acidic and contain certain enzymes.

During ejaculation, the bladder neck closes and the secretions from the vas, the seminal vesicles and the prostate are propelled through the urethra. "Retrograde ejaculation" is a condition that occurs when the bladder neck does not close and the secretions are propelled into the bladder. This can be detected through urinalysis, which will show sperm in the urine.

Fertilization
Once sperm are deposited in the vagina, they must pass through the cervical mucus, swim through the uterus and enter into the fallopian tubes. During this passage, the sperm undergo a series of changes and reactions that attract the sperm to the egg and make them capable of penetrating the layer of cells that surrounds the egg, as well as the zona pellucida, the thick coating of the egg. Part of this process is what is called the acrosome reaction, during which the cap over the head of the sperm dissolves, exposing enzymes that aid in penetrating the layers around the egg.

As a sperm is attracted to the egg and makes contact, it becomes much more vigorous. When one sperm penetrates the zona pellucida, it fuses with the egg cell membrane and enters the cytoplasm. The "zona reaction" then occurs; this is a release of substances just below the cell membrane that prevent penetration by another sperm.

Clearly, there is a complex series of steps and reactions that must take place in the sperm to allow it to reach and penetrate the egg. Any one of these reactions can go wrong. The bottom line is that the more numerous the sperm, the better their motility, and the more normal they appear, the better the chance that fertilization will take place.

Defects in Male Fertility: First Step - Semen Analysis
In most cases, when a couple is having trouble conceiving, they will consult their primary care physician or the woman's gynecologist for a preliminary evaluation. The next step would be for the man to have a semen analysis. This should be done at a facility that has the technical expertise and depth of experience to do a reliable test. For an optimal specimen, the man is advised to abstain from ejaculation for 2-3 days. It is better if the sample is then given to the laboratory as soon as possible after ejaculation. The sample is examined for volume, pH, sperm concentration, motility and morphology, and other characteristics. The normal ranges for these results are given below.

Table 1.
Semen Analysis Values: Normal and Subfertile.
  WHO criteria
Normal fertility		 Guzick Fertile cutoff Guzick Subfertile cutoff
Volume 1.5 - 5.5ml    
pH 7.2 - 7.8    
Concentration (millions/ml) <20 x 106/ml <48 x 106/ml <13.5 x 106/ml
Motility Percentage >50% >63% <32%
Percent normal Morphology >30% (WHO) criteria    
Percent normal Morphology >14% strict criteria >12% <9%

Diagnostic Terms Related to Semen Analysis
The following terms may come up in a discussion with a doctor about semen characteristics. They are listed along with their technical definitions.
  • Azoospermia: no sperm in semen
  • Oligospermia: very few sperm in semen <20 x 106/ml (WHO)
  • Severe oligospermia <5 x 106/ml
  • Asthenospermia: poor motility of sperm
  • Teratospermia: abnormal sperm forms <30% (WHO), <14% (Kruger)
Other Characteristics and Elements of Semen

Volume and pH
Ten percent of semen volume consists of secretions from the testis. The seminal vesicle contribution to the semen is alkaline and 70% of the total; the prostate contribution is acidic and 20% of the total. If the semen analysis shows that the semen is small in volume and acidic, that means that there is no contribution from the seminal vesicles, which may be absent or blocked. If there are no sperm as well, the ejaculatory ducts could be absent or blocked. If the pH (acidity) and volume are normal, but there are no sperm, there is either a physical blockage in the vas/epididymis or testis sperm production is severely diminished or absent.

Round Cells
These cells could be leukocytes, immature forms of sperm or exfoliated epithelial cells. They can be identified by special staining. There should be fewer than one million leukocytes/ml and five million total round cells/ml in a specimen. Excess leukocytes could indicate active infection or inflammation. Large numbers of immature sperm forms may indicate a defective maturation process.

One potential cause of infertility that is receiving more research attention lately is the presence of what are called reactive oxygen species (ROS) in the semen. Although some amounts of these substances are normal, in excess they damage sperm and can impair fertility. There is a delicate balance between antioxidants in the seminal plasma and the ROS. Both leukocytes and immature sperm forms can increase ROS and upset that balance.

Antisperm Antibodies
Sperm cells are kept isolated from the rest of the male body by the blood-testis barrier. If this barrier is breeched, antisperm antibodies can develop. Two tests used to detect these antibodies in a semen specimen are the immunobead test (IBT) and the mixed antiglobulin reaction (MAR) test. The tests are positive if there is a greater than 50% antibody coating of the motile sperm. The antibodies cause sperm to clump together and this can affect sperm motility. How much of a causative factor antibodies represent is hard to calculate, however, as some normally fertile men do have antisperm antibodies.

Semen Analysis and Fertility
In a large study of new couples seeking help with infertility, about 25% of the men had abnormal semen analysis results, as judged by the WHO (World Health Organization) Criteria. Azoospermia was found in 4.2% and 8.0% had severe oligospermia (<5 x 106/ml).

In another study from 1987, 50% were categorized as "no demonstrable cause" and half of the remaining 50% were categorized as "idiopathic." In that study, 75% of male factor infertility problems were either undiagnosable or in the case of a sperm abnormality, no cause could be found. In the cases where a cause could be identified, there was no one, overwhelming common cause.

Most of the identifiable causes were in single digit percentages. They included genetic, congenital, endocrine, iatrogenic (i.e., caused by medical treatment), and hormonal causes.

In the cases where a cause could be identified, there was no one, overwhelming common cause.

A review published in 2003 firmly states that 50% of male infertility is unexplained. It is believed, however, that many of the male factor infertility cases will be shown, one day, to have a genetic basis.

Examining a Man with Infertility
An abnormality in the semen analysis triggers a focused medical evaluation of the male partner. The examiner would look for the key screening points below in the man's medical history and do a genital examination.

Table 2.
Key Points of the Male Infertility Work-up: History and Physical Examination.
History
  • Systemic illnesses
  • Cancer, chemotherapy, radiation treatment
  • Urogenital system: surgery: hernia repair, undescended testicle(s), vasectomy
  • Trauma, torsion. Infection: epididymitis, orchiditis
  • Sexual history: function; sexually transmitted disease
  • Occupation, hobbies
Family History
  • Infertility, cystic fibrosis, other genetic conditions that may be passed on
Medications & Drugs
  • Prescription, recreational, anabolic steroids
    • Genital physical exam
    • Scars: surgical, post trauma
    • Testicular size (normal = 4.0-5.5 X 2.5 X 2.5 cm)
    • Epididymis
    • Vas deferens
    • Varicocele
    • Signs of infection
Using Semen Analysis to Detect Causes of Infertility
Although a profoundly depressed or absent sperm count in the semen is found in a small percentage of men, a determination of the cause of those very low sperm counts can now be made in the majority of cases. Some patients can be helped by corrective surgery, while for other impediments, caused by genetic mutations, it is important that the couple know about them as they make decisions about childbearing.

Azoospermia
Azoospermia is the complete absence of sperm in the semen and is seen in 2-4% of infertile males. Azoospermia could be caused by absent or extremely poor testicular function, in which case it is called nonobstructive azoospermia, or by a blockage in the genital tract, in which case it is called obstructive azoospermia.

Obstructive Azoospermia
The initial semen analysis is a good clue to the diagnosis of obstructive azoospermia because if the block is located at the level of the ejaculatory ducts, the semen will consist only of prostatic secretions. The volume would be very low, usually <1 ml and pH would be acidic. If the blockage is in the vas deferens or epididymis, the semen will have normal volume and alkaline pH but no sperm.

Low Volume, Low pH Azoospermia

Ejaculatory Duct Obstruction
In this case, the semen only contains prostatic fluid and has low volume and low pH. Both the vas deferens and the epididymis are full and firm to the touch. Testis size is normal. A prostatic cyst blocking the ejaculatory ducts could cause this condition. This can be diagnosed by ultrasound. Surgical removal of the obstruction may restore fertility.

Congenital Bilateral Absence of the Vas Deferens (CBAVD)
The semen volume is low (<1cc) and pH is less than 7. The vas deferens cannot be felt and only the head or a portion of the epididymis can be felt. The testicles are normal size. In men with these results, the vas deferens, the latter two thirds of the epididymis and the seminal vesicles have not developed normally, usually because of a genetic defect.

Thirty to 50% of men with obstructive azoospermia have congenital bilateral absence of the vas deferens (CBAVD). The most common genetic defect in these men is a mutation in the cystic fibrosis transmembrane regulator (CFTR) gene on chromosome 7. The normal function of CFTR is thought to be crucial to maintaining genital duct patency during very early development. Almost all (98%) of men with cystic fibrosis have CBAVD.9 Nearly 70% of men with CBAVD have at least one CFTR mutation. Some of these men may have two mutations with variable expression so that classical cystic fibrosis does not develop.5 CBAVD may be the only manifestation of CFTR mutation in these men. Over 1000 mutations that affect the CFTR gene have been identified. CBAVD is also seen in men with genetic mutations that cause other defects of the genitourinary tract, like unilateral renal agenesis.

All patients with CBAVD should have genetic testing for CFTR mutations, transrectal ultrasound to determine the anatomy of the seminal vesicles, which are usually absent but can be cystic and dilated, and a renal ultrasound to check for renal agenesis.

Men with CBAVD can father children using assisted reproductive technology (ART) procedures, percutaneous or microsurgical epididymal duct aspiration (PESA or MESA) or testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI). See below.

Genetic Counseling and CBAVD
Cystic fibrosis (CF) is caused by an autosomal recessive gene mutation. If the man has two copies of this gene mutation and the woman has one copy of a CFTR mutation (is a carrier), 50% of the children will have two copies of a mutation and a high risk for classical CF and 50% will be carriers. If she does not have a CFTR mutation, all the children will be carriers because they all inherit one copy from the father. Approximately 4% or one in twenty-five women may have a CF mutation. The woman should be tested for a CFTR mutation, so that the couple will know what to expect. One option is preimplantation diagnosis-a cell is removed from the embryo and tested for CFTR mutations. With that knowledge the couple may opt not to transfer an embryo that is homozygous for CFTR mutations.

Normal Volume, Normal pH Obstructive Azoospermia
In this case, the semen volume is 1.5ml or greater and the pH is 7.2 or more. Testicular size is normal. Depending on the level of obstruction, the vas and the epididymis can be firm to the touch. Testicular size and consistency are normal. The man may have a history of surgeries such as vasectomy, bilateral hernia repair, or bilateral epididymitis.

Many men with this condition can be treated with microsurgery, bypassing the obstruction and reconnecting vas to vas or epididymis to vas. Repair is not always possible, so the removal of sperm-containing fluid for storage in a sperm bank (cryopreservation) may be considered as part of the procedure.

Normal Volume, Normal pH Nonobstructive Azoospermia or Severe Oligospermia
In men with these results, the vas and epididymis are normal; the testicles may be normal or small and soft. They may contain sperm, but at such low levels that sperm does not appear in the semen (azoospermia) or appears only in very small numbers (severe oligospermia).

There are many possible causes of testicular failure. A number of chromosomal defects have been shown to cause infertility in males, including abnormal chromosome number, microdeletions or translocations. Other possible causes include maturation arrest of sperm, absence of the primordial germ cells ("Sertoli Cell Only Syndrome") or defective or absent androgen receptors ("androgen insensitivity syndrome"). There can be defects in pituitary hormone receptors or secretion. I will focus on the two most common chromosomal defects, microdeletions in the long arm of the Y chromosome and Klinefelter's syndrome.

Chromosomal Abnormalities in Men with Nonobstructive Azoospermia and Severe Oligospermia

Y Chromosome Microdeletions
In the mid 1990s, an important genetic defect associated with azoospermia and severe oligospermia was identified. On the active arm of the Y chromosome there are three areas, called "azoospermia factor" AZF a, b and c, that are critical to sperm development. Together, deletions in these three areas are found in 16% of cases with azoospermia and 14% of cases with severe oligospermia. A deletion of AZFc is the most common of the three. Sperm can be retrieved from the testes in some of these patients for in vitro fertilization. One problem is that this genetic defect will be passed on to all male children. Couples dealing with this issue should discuss this fully with their doctor.

Klinefelter's Syndrome
Men with Klinefelter's syndrome have an extra Y chromosome. This abnormality is associated with deficient Leydig cell production of testosterone. This usually means that the male will not experience a normal puberty. He will become tall, will lack secondary sex characteristics and may have mental deficiency. Men with Kleinfelter's syndrome are usually treated at puberty by being put on androgen replacement. Sometimes, they will have sufficient testosterone for a seemingly normal puberty and libido, but have insufficient testosterone for sperm production. On physical exam, the testicles are small and firm. Testosterone level is low and FSH and LH are elevated. Sperm can be retrieved from the testicular tissue of some of these men for in vitro fertilization.

Other Factors and Male Fertility

Cryptorchidism
When the testes do not descend into the scrotum and remain in the groin or abdomen, they do not develop normally. This condition is usually noticed in infancy and corrected. Authorities recommend that orchiopexy, a surgical procedure that locates the undescended testicle and places it in the scrotum, be done by two years of age. But even after timely orchiopexy, some men will have azoospermia or oligospermia because of incomplete maturation at a very early stage of sperm development. The reason is that sometimes there is more to cryptorchidism than just a defect in the physical location of the testis. There may be other genetic abnormalities as well.

Varicocele
Varicoceles are dilated veins that often can be both seen and felt in the scrotum. They develop at the time of puberty and usually occur on the left side. They are present in over 15% of the male population. When you look at men who have had an abnormal semen analysis, 40% have a varicocele.

Most men who have infertility and a varicocele have more than one abnormal semen characteristic (e.g., concentration, motility, or morphology). Testicular volume may be diminished on the affected side. One possible cause is elevated testicular temperature. Although many agree that varicoceles can adversely affect the testis, some experts question whether repairing the varicocele in a man with impaired fertility will solve his fertility problem. Different studies that have come down on different sides of this question.10 Since many men with varicoceles have normal fertility potential, a varicocele should not be repaired simply because it is present, but only if there is reason to believe that it will improve fertility. On the other hand, many pediatric urologists suggest that an adolescent with a varicocele and with a small testis on the affected side may experience "catch up growth" if the varicocele is corrected. Whether this will prevent future fertility problems remains to be determined.

Heat: Is a warm testis a sick testis?
Spermatogenesis works best at a temperature several degrees below normal body temperature. This is the reason that the testes are located outside the abdomen, in the scrotum. A testis that remains in the abdomen and one that is adjacent to a tangle of veins will be warmer, and this increased temperature is thought to cause testicular damage or dysfunction in cases of cryptorchidism and varicocele. But should tight underwear, tights, athletic supporters and hot tubs be forbidden in the name of preserving fertility? The benefit of changing clothing is doubtful, but avoiding hot tubs and saunas, particularly if the sperm count is borderline, is probably a good idea when trying for a pregnancy.

...Avoiding hot tubs and saunas, particularly if the sperm count is borderline, is probably a good idea when trying for a pregnancy.

Drugs
A number of drugs are associated with male infertility. An exhaustive list would be extremely long; suffice to say that anyone with a fertility problem should review, with their doctor, all prescription, over-the-counter and recreational drugs that they use. A few common examples are given in Table 3.

Table 3.
Some Drugs Affecting Male Fertility.
  • Anabolic steroids
  • Chemotherapy drugs
  • Ketaconazole
  • Nitrofurantoin
  • Spironolactone
  • Tricyclic antidepressants
  • Major and minor tranquillizers
  • Phenytoin
  • Narcotics
  • Marijuana and cocaine
  • Nicotine
  • Alcohol
Cancer Treatment and Male Fertility
Both chemotherapy and radiation affect rapidly dividing cells in the body and can destroy or severely compromise fertility. Radiation can cause chromosomal damage as well. A man who anticipates fathering children should consider cryopreserving (banking) his sperm before undergoing cancer treatment.

Men who have already had cancer treatment and have azoospermia may still have viable sperm in the testes that can be recovered by epididymal duct aspiration or by testicular sperm extraction.

Toxins
Environmental and workplace hazards can affect male fertility. Consult http://www.cdc.gov/niosh/programs/crcd/ for more information.

Treating Male Infertility
In some instances, surgery directly on the genital tract can restore normal fertility. Examples are correction of azoospermia by relieving an obstruction; reversal of a vasectomy; bypassing epididymal scarring; and removing a prostatic cyst. When these repair procedures are undertaken, the surgeon may also retrieve a sperm specimen for cryopreservation, because not all surgeries will be successful.

Some men with hypothalamic/pituitary hormone deficiencies can be treated with gonadotropin therapy.

Maximizing Male Fertility
In most cases, the aim of treatment is to maximize male fertility potential. As mentioned before, two to three days of abstinence before intercourse increases the volume and sperm content of the ejaculate.

Sperm can also be separated from the other elements in the semen and concentrated. This concentrated specimen is used for a procedure called intrauterine insemination (IUI). In IUI, the cervix is bypassed and the sperm is released high in the uterine cavity. It is timed with ovulation, either natural or stimulated.

Cryopreservation
Sperm specimens can be frozen ("banked") for future use. High quality cryopreserved sperm are nearly as viable as fresh specimens, although there is always some fall-off in quality. With poorer specimens, the fall-off will be greater.

Special Assisted Reproductive Technologies to Boost Male Fertility

Surgical Sperm Recovery
I have mentioned above that when there is an anatomical blockage or very poor testicular function, sperm can be retrieved surgically directly from the testis.

The best method is to aspirate the semen from the epididymal duct because that would contain the most mature sperm. Aspiration from a seminiferous tubule would be next, followed by biopsy of actual testicular tissue. Special separation procedures are required to extract sperm from testicular tissue. In all cases, sperm not used for an immediate fertilization attempt should be cryopreserved so that the procedure would not have to be repeated.

These procedures all have acronyms and are listed below. Which one is the right one depends on the judgment of the individual surgeon and on clinical circumstances.

PESA: Percutaneous Epididymal Sperm Aspiration
MESA: Microsurgical Epididymal Sperm Aspiration
TESA: Testicular Sperm Aspiration
TESE: Testicular Sperm Extraction

Intracytoplasmic Sperm Injection (ICSI)
Some male factor infertility is caused by defects in the final steps of fertilization, that is, the processes that cause attraction to the egg, increased motility, the penetration of the zona pellucida and binding to the egg cell membrane. Sperm with these defects cannot fertilize an egg in vitro, where the egg and sperm are simply placed together.

In the late 1980s, several techniques were developed that use extremely fine micropipettes to inject the sperm through the barrier around the egg and achieve fertilization. In partial zonal dissection (PZD), the sperm is placed partly through the zona pellucida and in subzonal insemination (SUZI), the sperm is placed just beneath the zona. There are still sperm, however, that are unable to enter the egg using these procedures.

With intracytoplasmic sperm injection (ICSI), the sperm is injected directly into the egg cytoplasm. In 1992, three full-term pregnancies using this technique were reported.11 Now ICSI has largely replaced the other micropipette procedures, PZD and SUZI, and is used in about half of the in vitro fertilization-embryo transfer (IVF-ET) cycles reported by the CDC.

Some have raised concerns about damage to the egg cytoplasm and about other substances being injected along with the sperm. Long-term studies are underway to follow children resulting from this procedure to detect any developmental and genetic problems. One study of two-year-old children did not find any significant differences compared with naturally conceived children. There was, however, a trend toward more genital tract abnormalities in males. Further follow-up will have to be done to determine whether there is an increased prevalence of fertility problems among the male children conceived by ICSI.

Summary and Conclusions
Male factor infertility is increasingly diagnosed as the primary problem in infertile couples, perhaps in as many as 40% of all cases. The causes of male infertility range from obstructive to environmental to developmental to genetic problems. As genetic medicine research progresses, more genetic causes are being identified. Today, only a small portion of infertile males can be cured and the cause of their infertility completely corrected. Short of that, doctors do have a wide range of techniques and procedures that can maximizing male fertility. The most advanced procedures, for example, testicular sperm extraction and intracytoplasmic sperm injection, now allow many formerly "sterile" men to become fathers.