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In This Report

•	Highlights
•	Introduction
•	Male Reproductive System...
•	Sperm Abnormalities
•	Causes
•	Diagnosis
•	Treatment
•	Assisted Reproductive Techn...
•	Complications of ART
•	Other Treatments
•	Resources
•	References

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Infertility in men

Highlights

Age and Male Infertility

Men who wait until later in life to have children may have a more difficult time fathering a successful pregnancy. According to a 2006 study in the Proceedings of the National Academy of Sciences, the genetic quality of sperm declines as a man ages. Previous studies have indicated that aging negatively affects sperm counts and sperm motility (the sperm’s ability to move). This new research suggests that poor sperm motility is linked to DNA fragmentation, which increases the chances for male infertility and the likelihood of fathering children with genetic problems. Researchers found that the rare genetic mutations associated with dwarfism increased by 2% with every year of a man’s age.

Obesity and Male Infertility

A 20-pound increase in a man’s weight raises his chance for infertility by 10%, according to a 2006 study in Epidemiology. In a study of nearly 1,500 couples, researchers found that men with a higher body mass index were significantly more likely to be infertile than normal-weight men. Previous studies have shown that obesity is also associated with female infertility. Some studies suggest that overweight and obese men may have poorer sperm quality.

Cancer and Male Infertility

Freezing and storing sperm for later use (sperm cryopreservation) is the best method for preserving fertility in men undergoing cancer treatments, advises the American Society of Oncology’s (ASCO) 2006 guidelines. Investigational techniques include testicular cryopreservation -- the freezing and storing of testicular tissue. ASCO recommends that men with cancer consult a reproductive specialist to discuss all possible fertility preservation options.

Intracytoplasmic Sperm Injection (ICSI)

Children conceived with ICSI are healthy and develop normally, according to research presented at a 2006 reproductive meeting. Researchers studied 8-year-old children conceived with ICSI and found no major medical differences between them and children conceived naturally. ICSI is one of the main assisted reproductive technologies used for couples with male-based infertility.

Introduction

Infertility is the failure of a couple to become pregnant after one year of regular, unprotected intercourse. In both men and women the fertility process is complex. Even under ideal circumstances, the probability that a woman will get pregnant during a single menstrual cycle is only about 30%. And, when conception does occur, only 50 - 60% of pregnancies advance beyond week 20. In many cases, infertility is caused by a combination of problems in both partners that conspire to prevent conception from occurring.

About 8 - 10% of couples of reproductive age experience infertility, and in around 40% of these cases male infertility is the major factor. Another 40% of infertility problems are caused by abnormalities of the woman's reproductive system, and the remaining 20% involve couples who both suffer reproductive difficulties.

Infertility affects one in 25 American men. More than 90% of male infertility cases are due to low sperm counts, poor sperm quality, or both. Whether sperm counts are declining overall in industrialized countries is a controversial issue. However, over the last few years the number of assisted reproductive procedures that target male infertility have increased, while female procedures have declined.

The male reproductive system creates sperm that is manufactured in the seminiferous tubules within each testicle. The head of the sperm contains the DNA, which when combined with the egg's DNA, will create a new individual. The tip of the sperm head is the portion called the acrosome, which enables the sperm to penetrate the egg. The midpiece contains the mitochondria which supplies the energy the tail needs to move. The tail moves with whip-like movements back and forth to propel the sperm towards the egg. The sperm have to reach the uterus and the fallopian tube in order to fertilize a woman's egg.

Male Reproductive System

Male fertility depends on the proper function of a complex system of organs and hormones:

• The process begins in the area of the brain called the hypothalamus-pituitary axis, a system of glands, hormones, and chemical messengers called neurotransmitters, all of which are critical for reproduction.
• The first step in fertility is the production of gonadotropin-releasing hormone (GnRH) in the hypothalamus, which prompts the pituitary gland to manufacture follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
• FSH maintains sperm production, and LH stimulates the production of the male hormone testosterone.
• Both sperm and testosterone production occurs in the two testicles, or testes, which are contained in the scrotal sac (the scrotum). (This sac develops on the outside of the body because normal body temperature is too high to allow sperm production.)

The male reproductive structures include the penis, the scrotum, the seminal vesicles, and the prostate.

Sperm are manufactured in several hundred microscopic tubes, known as seminiferous tubules, which make-up most of the testicles.

Surrounding these tubules are clumps of tissue containing so-called Leydig cells. Here, testosterone is manufactured.

Sperm

Sperm Development. The life cycle of sperm consists of a remarkable journey that depends on hormonal signals combined with a mechanical process. It takes about 74 days:

• Sperm begin partially embedded in nurturing amoebae-like cells known as Sertoli cells, which are located in the lower parts of the seminiferous tubules.
• As they mature and move along, they are stored in the upper part of the tubules. Young sperm cells are known as spermatids.
• When the sperm has completed the development of its head and tail, it is released from the cell into the epididymis. This remarkable C-shaped tube is 1/300 of an inch in diameter and about 20 feet long. It loops back and forth on itself within a space that is only about one and a half inches long. The sperm's journey through the epididymis takes about three weeks.
• The fluid in which the sperm is transported contains sugar in the form of fructose, which provides energy as the sperm matures. In the early stages of its passage, the sperm cannot swim in a forward direction and can only vibrate its tail weakly. By the time the sperm reaches the end of the epididymis, however, it is mature and looks like a microscopic squirming tadpole.
• At maturity, each healthy sperm consists of a head that contains the man's genetic material, his DNA, and a tail that lashes back and forth at great speed to propel the head forward at about four times its own length every second. The ability of a sperm to move forward rapidly and straight is probably the most significant determinant of male fertility.

Ejaculation. When a man experiences sexual excitement, nerves stimulate the muscles in the epididymis to contract, which forces the sperm out through the penis:

• In the penis, the sperm first pass into one of two rigid and wire-like muscular channels, called the vasa deferentia. (A single channel is called a vas deferens.)
• Muscle contractions in the vas deferens from sexual activity propel the sperm along past the seminal vesicles. These are clusters of tissue that contribute fluid, called seminal fluid, to the sperm. The vas deferens also collects fluid from the nearby prostate gland. This mixture of various fluids and sperm is the semen.
• Each vas deferens then joins together to form the ejaculatory duct. This duct, which now contains the sperm-containing semen, passes down through the urethra. (The urethra is the same channel in the penis through which a man urinates, but during orgasm, the prostate closes off the bladder so urine cannot enter the urethra.)
• The semen is forced through the urethra during ejaculation, the final stage of orgasm when the sperm is literally shot out of the penis.

Click the icon to see an image of the vas deferens.

Semen. In addition to providing the fluid that transports the sperm, semen also has other benefits:

• It provides a very short-lived alkaline environment to protect sperm from the harsh acidity of the female vagina. (If the sperm do not reach the woman's cervix within several hours, the semen itself becomes toxic to sperm and they die.)
• It contains a gelatin-like substance that prevents it from draining from the vagina too quickly.
• It contains sugar in the form of fructose to provide instant energy for sperm locomotion.

The Path to the Egg. The sperm's passage to the egg is a perilous journey.

• Usually about 100 - 300 million sperm are delivered into the ejaculate at any given time. Even under normal conditions, however only about 15% of these millions of sperm are sound enough to fertilize an egg.
• To compound the problem, after the stress of ejaculation, only about 400 sperm survive the orgasm to complete the journey.
• Out of this number, a mere 40 or so sperm survive the toxicity of the semen and the hostile environment of the vagina to reach the vicinity of the egg. Normally, the cervical mucus forms an impenetrable barrier to sperm. However, when a woman ovulates (releases her egg, the oocyte), the mucous lining thins to allow sperm penetration.
• Sperm that manage to reach the mucous lining in the woman's cervix (the lower part of her uterus) must survive about four more days to reach the woman's fallopian tubes. (Here, the egg is positioned for fertilization for only 12 hours each month.)
• The few remaining sperm that penetrate the cervical mucus and are able to reach the fallopian tubes become capacitated.
• Capacitation is a one-time explosion of energy that completes the sperm's journey. It boosts the motion of the sperm and triggers the actions of the acrosome, a membrane that covers the head of the sperm and resembles a warhead. The acrosome is dissolved, and enzymes contained within it are released to allow the sperm to drill a hole through the tough outer coating of the egg.
• In the end, only one sperm gets through to fertilize the egg.

Click the icon to see an image of the uterus.

Sperm Abnormalities

More than 90% of male infertility cases are due to low sperm counts, poor sperm quality, or both. In 30 - 40% of cases of sperm abnormalities, the cause is unknown. It may be the end result of one or more factors that include chronic illness, malnutrition, genetic defects, structural abnormalities, and environmental factors. Partial obstruction anywhere in the long passages through which sperm pass can reduce sperm counts. In one study, obstruction was believed to be a contributing factor in over 60% of low sperm count cases. Obstruction itself can be caused by many factors.

Defining Sperm Abnormalities

Sperm abnormalities are categorized by whether they affect sperm count, sperm quality, or sperm shape.

Low Sperm Count (Oligospermia)

In the past, a sperm count of less than 40 million/mL in the ejaculate was believed to cause infertility. Now, however, if the woman is fertile and young, a count as low as 10 million can often accomplish conception over time, even without treatment. In fertilization clinics, men with low sperm counts report fertilization rates of about 30%, while those with average sperm counts have rates between 60 - 80%. Sperm count varies widely over time, and temporary low counts are common. Therefore, a single test that reports a low count may not be a representative result.

Poor Sperm Motility (Asthenospermia)

Sperm motility is the sperm's ability to move. If movement is slow, not in a straight line, or both, the sperm have difficulty invading the cervical mucous or penetrating the hard outer shell of the egg. If 60% or more of sperm have normal motility, the sperm is at least average in quality. If less than 40% of sperm are able to move in a straight line, the condition is considered abnormal. Sperm that move sluggishly may also have genetic or other defects that render them incapable of fertilizing the egg. An important 2001 study identified a protein in the tail of the sperm called CatSper, which might play a central role in the ability of the sperm to swim and penetrate the egg.

Abnormal Sperm Morphology (Teratospermia)

Morphology refers to the shape and structure of an object. Morphology may be even more important than count or motility in determining potential fertility. Abnormally shaped sperm cannot fertilize an egg. About 60% of the sperm should be normal in size and shape for adequate fertility.

The perfect structure is an oval head and long tail. Abnormally shaped sperm may include a number of variations:

• A very large round head. (In one study, if 14% or more of sperm had round enlarged heads, the chances for pregnancy fell to about 20%. Such an abnormality indicates early unraveling of genetic material.)
• An extremely small pinpoint head
• A tapered head
• A crooked head
• Two heads
• A tail with kinks and curls

Genetic Fragmentation

Sperm carry half the genetic material necessary to make a complete human being. (The egg holds the other half.) Genes are contained in the rod-like structures called chromosomes. The genes themselves are made up of chains of molecules called DNA, which carry the information that defines a human. Genetically fragile sperm are important factors in male infertility. Such sperm have fragmented DNA chains, which make them less capable of fertilization and may also contribute to low quality.

Causes

In a 2001 study, the causes of infertility in men seeking to conceive included:

• Vasectomy. In the study, 56% of men were seeking a reversal of this procedure. Thirty years ago, this was a factor in only 5% of men seeking help for fertility.
• Varicocele (14%). A network of veins carries blood away from the testicles and back up into the body. If these veins become enlarged, twisted, and swollen (similar to varicose veins in the leg), this condition is termed a varicocele. Varicoceles can impair testicular function and fertility.
• Unknown infertility (8%).
• Absence of sperm (6%). There are many biologic and environmental factors that can lead to low sperm count. For instance, abnormalities in production or obstruction of the tubes that carry sperm can reduce sperm levels. A condition called Sertoli cell-only syndrome is one in which the cells that produce sperm (the Sertoli cells) are absent. This can be a congenital problem that a man is born with or caused by infection, injury, medication, radiation, or genetics. In addition, other conditions may cause infertility in men.

Age

The effect of aging on male fertility is not totally clear. However, growing evidence suggests that it may be a factor (although not to the extent that it is in women). This evidence indicates that age-related sperm changes in men are not abrupt, but are a gradual process. Aging can adversely affect sperm counts and sperm motility (the sperm’s ability to swim quickly and move in a straight line). A 2006 study also suggested that the genetic quality of sperm declines as a man ages. The researchers found that poor sperm motility was associated with DNA fragmentation. This led to some older men having an increased risk of passing on gene mutations that cause dwarfism and possibly other genetic diseases.

Temporary and Lifestyle Causes of Low Sperm Count

Nearly any major physical or mental stress can temporarily reduce sperm count. Some common conditions that lower sperm count, temporarily in nearly all cases, include:

Emotional Stress. Stress may interfere with the hormone GnRH and reduce sperm counts.

Sexual Issues. In less than 1% of cases, impotence, premature ejaculation, or psychological or relationship problems contribute to male infertility, although these conditions are usually very treatable. Lubricants used with condoms, including spermicides, oils, and Vaseline, can affect fertility. Astroglide, Replens, or mineral oil may not be as harmful to sperm. However, oil-based lubricants can damage latex condoms and should be avoided.

Testicular Overheating. Overheating, such as from high fevers, saunas, and hot tubs, may temporarily lower sperm count. Persistent exposure to high temperatures during work may impair fertility. Several studies have found no negative effects on fertility from wearing tight trousers, briefs, or athletic supports, even every day.

Substance Abuse. Cocaine or heavy marijuana use appears to temporarily reduce the number and quality of sperm by as much as 50%. Sperm actually have receptors for certain compounds in marijuana that may impair the sperm's ability to swim and also inhibit their ability to penetrate the egg. Alcohol does not appear to affect fertility, unless it is so abused that it causes liver damage.

Smoking. Smoking impairs sperm motility, reduces sperm lifespan, and may cause genetic changes that affect the offspring. One 2002 trial found that men or women who smoke have lower success rates with assisted reproductive technologies. An earlier study reported that men who smoke also have lower sex drives and less frequent sex.

Malnutrition and Nutrient Deficiencies. Deficiencies in certain nutrients, such as vitamin E, vitamin C, selenium, zinc, and folate, may be particular risk factors for infertility

Obesity. Obesity may be a risk factor for male infertility. A 2006 epidemiological study found that a 20-pound increase in a man’s weight increased the chance for infertility by about 10 percent.

Bicycling. Bicycling has been linked to impotence in men and also may affect fertility. Pressure from the bike seat may damage blood vessels and nerves that are responsible for erections. Mountain biking, which involves riding on off-road terrain, exposes the perineum (the region between the scrotum and the anus) to more extreme shocks and vibrations and increases the risk for injuries to the scrotum. One study found that men who mountain bike are far more likely to have scrotal abnormalities, including calcium deposits, cysts, and twisted veins. Men who cycle can reduce such risks by:

• Taking frequent rests while biking
• Wearing padded bike shorts
• Using a padded or specially contoured bike seat that is raised high enough and sits at the proper angle

Genetic Factors

Problems in the genes that regulate male fertility and in the genetic material of sperm itself are important contributors to infertility problems in men. In fact, even in men with no known fertility problems, 19% of the sperm are genetically defective. Certain inherited medical conditions also contribute to male infertility. Defective genes themselves can be inherited, produced by environmental assaults (such radiation exposure), or both. Of some concern is the possibility that these mutations will be passed to offspring in men who undergo fertilization techniques that retrieve sperm and directly fertilize the egg. (Under natural conditions, genetically abnormal sperm would be very unlikely to reach and fertilize the egg.)

Defective Genetic Material. Sperm carry half the genetic material necessary to make a human being. Infertile men have been reported to have a relatively high percentage of sperm with broken or damaged DNA (the molecular chain that makes up a gene).

Genetic Factors Specifically Affecting Sperm Production or Quality. Abnormalities in genes that specifically regulate sperm production and quality are major factors in male infertility. Some research suggests that about 10% of cases of male infertility may be due to problems, most likely genetic, in the acrosome. The acrosome is the enzyme-filled membrane cap on the sperm -- its warhead -- that is critical for piercing the egg. In one study, pregnancy was impaired if 7% or more of sperm had abnormalities in the acrosome.

Inherited Disorders that Affect Fertility. Certain inherited disorders can impair fertility. Examples include:

• Cystic fibrosis patients often have missing or obstructed vas deferens (the tubes that carry sperm). In fact, men whose infertility is caused by an inborn missing vas deferens have a 60% chance that they carry the gene for cystic fibrosis (even if they don't have the disease itself).
• Klinefelter syndrome patients carry two X and one Y chromosomes (the norm is one X and one Y), which leads to the destruction of the lining of the seminiferous tubules in the testicles during puberty, although most other male physical attributes are unimpaired.
• Kartagener syndrome, a rare disorder that is associated with a reversed position of the major organs, also includes immotile cilia (hair-like cells in lungs and sinuses that have a structure similar to the tails of sperm). Sperm motility may also be impaired by this condition.
• Polycystic kidney disease, a relatively common genetic disorder that causes large cysts to form on the kidneys and other organs during adulthood, may cause infertility as the first symptom if cysts develop in the reproductive tract.

Environmental Assaults

Exposure to toxins, chemicals, or infections may reduce sperm count either by direct effects on testicular function or by altering hormone systems, although the extent of the impact and specific environmental assaults involved are often controversial. Some experts believe it is contributing to a general worldwide decline in male fertility.

Free Radicals (Oxidants). The primary suspects in the link between environmental assaults and infertility are free radicals, also called oxidants. These are unstable molecules, usually containing oxygen, that are released as a by-product of many natural chemical processes in the body. Infections, chemicals, and other environmental assaults can produce high levels of these particles. High levels may even affect the genetic material in cells. Sperm are particularly vulnerable to the damaging effects of this oxidation process. There have been reports that significant levels of oxidants occur in the semen of about 25% of infertile men.

Exposure to Estrogen-Like and Hormone-Disrupting Chemicals. European studies have increasingly reported a worsening in male reproductive health and an increase in testicular and prostate cancers. Many investigators strongly suspect environmental causes, particularly excessive chemicals that disrupt hormones, as a major cause for both these events. Estrogen-like chemicals found in pesticides and other chemicals are of particular concern. Overexposure to estrogen in male animals reduces the number of Sertoli cells (the cells necessary for the initial development of sperm). Some hormone-disrupting chemicals under investigation include:

Treatment of prostate cancer varies depending on the stage of the cancer and may include surgical removal, radiation, chemotherapy, hormonal manipulation or a combination of these treatments.

• Bisphenol A is a widely used chemical found in plastic food containers and bottles that has provoked concern. It has potent estrogen-like effects in low dose. Use of the chemical in female rats has produced prostate abnormalities in their male offspring.
• Phthalates, chemicals used to soften plastics, are under particular scrutiny for their ability to disrupt hormones. Specific phylates of special concern include dibutyl phthalate (DBP), which is found in many products, including cosmetics and clay products sold to children (Fimo, Sculpey). Animals exposed to phylates have significantly impaired sperm count and abnormalities in their reproductive structures, such as the testes. In addition, there is some concern that exposure in pregnant women may affect the offspring,
• Organochlorines are compounds that combine chlorine and organic substances -- usually petrochemicals. Many have estrogen-like effects, including those previously used to make plastics (PCBs) and pesticides (DDT and p,p-DDE). Some, such as dioxins and furans, are byproducts of many chemical processes. Fortunately, most of these chemicals have been banned, but they were heavily used in manufacturing before 1970 and are still widespread in the environment. Studies report that when men had a history of moderate or high on-the-job exposure to pesticides containing organochlorines, their fertility rates were lower than men without such exposures. Studies have found a strong correlation between high levels of polychlorinated biphenyls (PCBs) or p,p-DDE with reduced sperm quality and quantity. In one of the studies, even men with healthy sperm with high organochlorine levels had a lower sperm count than those with lower levels of these compounds.

Most evidence on the hormone of chemical estrogens has occurred in animals and birds. Tests of single chemicals containing estrogen have reported little danger for people. Some studies suggest, however, that exposure to more than one of these chemicals may be very harmful. At this time, there is no strong evidence supporting a serious harmful effect in people who have normal exposure to these chemicals. Major efforts are underway to determine the extent of any possible harm from these chemicals.

Hydrocarbons and Other Industrial Chemicals. In a 2000 study, workers in a rubber factory who were chronically exposed to hydrocarbons (ethylbenzene, benzene, toluene, and xylene) had lower than average sperm counts and sperm qualities. (In a 2001 study, men who smoked and worked in petrochemical plants had particularly poor sperm quality.) Still, not all major studies have confirmed the effects of these chemicals, and evidence showing any significant effect on fertility is weak.

Exposure to Heavy Metals. Chronic exposure to heavy metals such as lead, cadmium, or arsenic may affect sperm quality. Trace amounts of these metals in semen seem to inhibit the function of enzymes contained in the acrosome, the membrane that covers the head of the sperm.

Radiation Treatments. X-rays and other forms of radiation affect any rapidly dividing cell, so cells that produce sperm are quite sensitive to radiation damage. Cells exposed to significant levels of radiation may take up to 2 years to resume normal sperm production and, in severe circumstances, may never recover.

Low Semen Levels

Men with fertility problems because of low semen levels when they ejaculate may have a structural abnormality in the tubes transporting the sperm. (A normal amount of semen is 2.5 - 5 mL, or about 1/2 - 1 teaspoon.)

Varicocele

A varicocele is an abnormally enlarged and twisted (varicose) vein in the spermatic cord that connects to the testicle. Varicoceles are found in 15 - 20% of all men and in 25 - 40% of infertile men, although it is not clear how or even if they affect fertility. They tend to occur more commonly (85%) on the left side. Some theories supporting their possible effect on infertility include:

Click the icon to see an image of a varicocele.

• Varicoceles may partially obstruct the passages through which sperm pass.
• Varicoceles may elevate temperature in the testes.
• Varicoceles may produce higher levels of nitric oxide, a substance that has beneficial effects on blood flow and other functions but which might, in excess, injure sperm.
• Varicoceles may block oxygen supply to the sperm.
• Varicoceles have been associated with abnormalities in cellular material in the sperm. One study suggested that some men may have genetic defects that cause both varicoceles and impaired sperm, rather than the varicocele itself causing infertility.

Some reports indicate that only varicoceles that are large enough to be felt (or palpable) may impact fertility. On the other hand, however, an 8-year study of men with and without varicoceles found no differences in sperm quality or in the ability to conceive. Furthermore, the few well-conducted studies on repair of varicoceles suggest that the procedure does not improve pregnancy rates. Their effect on fertility remains unclear.

Testosterone Deficiencies and Hypogonadism.

Hypogonadism is the general name for a severe deficiency in gonadotropin-releasing hormone (GnRH), the primary hormone that signals the process leading to the release of testosterone and other important reproductive hormones. Low levels of testosterone from any cause may result in defective sperm production.

Hypogonadism is uncommon and is most often present at the time of birth, usually the result of rare genetic diseases affecting the pituitary gland that may include selective deficiencies of the hormones FSH and LH, Kallman syndrome, or panhypopituitarism, in which the pituitary gland fails to make almost all hormones. It can also develop later in life from brain or pituitary gland tumors or as a result of radiation treatments. Defects in the gene on the X chromosome that regulates receptors that bind to androgens (male hormone) may also prove to be very important causes of male infertility.

Click the icon to see an image of the pituitary gland.

Autoantibodies

Autoimmunity is a condition in which antibodies of the immune system attack specific cells in the body, mistaking them for foreign microinvaders. In the case of male infertility, these so-called autoantibodies ("self" antibodies) target the sperm. Antibodies bind to specific parts of the sperm, such as the head or tail and, depending on the site of attachment, cause various problems:

• Sperm may stick together (agglutinate)
• They may fail to interact with cervical mucous
• They may be unable to penetrate the egg

Some experts believe that in most cases the presence of these antibodies will not prevent conception unless a large percentage of sperm are affected.

Vasectomy and Anti-Sperm Antibodies. Vasectomy, the primary sterility procedure in men, is the most common cause of sperm autoantibodies (also called anti-sperm antibodies). Experts believe their typical development is as follows:

• Vasectomy works by severing the vas deferens, the tube that carries sperm from the testicles to the urethra (which leads out of the penis).
• After vasectomy, sperm continue to be produced but, instead of being confined to the reproductive passages, they leak out into the body.
• Here, the immune system may perceive them as foreign invaders and develop antibodies to attack them.

Such antibodies often persist, even if a man restores sperm flow by a successful reversal procedure (vasovasostomy). The persistence of anti-sperm antibodies may result in infertility.

Click the icon to see an illustrated series detailing vasectomy.

Other Causes of Autoantibodies. Antibodies to sperm can also appear in men without previous vasectomies and have been reported to be present in 10% of all men with fertility problems. They may be linked to genital infections or injury, although the cause is usually not known.

Retrograde Ejaculation

Retrograde ejaculation occurs when the muscles of the urethra do not pump properly during orgasm and sperm are forced backward into the bladder instead of forward out of the urethra. Sperm quality is often impaired.

Retrograde ejaculation can be the consequence of several conditions:

• Surgery to the lower part of the bladder or prostate (the most common cause of retrograde ejaculation)
• Diabetes
• Multiple sclerosis
• Back surgery
• Spinal cord injury

Medications such as tranquilizers, certain antipsychotics, or hypertension medications also may cause temporary retrograde ejaculation.

Testicular Dysgenesis Syndrome and Other Physical or Structural Abnormalities

Any structural abnormalities that affect the testes, tubes, or other reproductive structures can have a profound effect on fertility.

Testicular Dysgenesis Syndrome. Testicular dysgenesis syndrome is a recently observed occurrence of three conditions -- impaired sperm production and quality, testicular cancer, and genital tract abnormalities. Environmental factors that increase damage from oxidants are believed to be responsible.

The genital abnormalities identified with this syndrome are undescended testes and hypospadias, each of which is associated with infertility:

• Undescended Testes (Cryptorchidism). In some cases, there is a failure of the testes to descend from the abdomen into the scrotum during fetal life. Cryptorchidism is associated with mild to severe impairment of sperm production. In one survey, 38% of men who as youngsters had two undescended testicles and 10% of men with one undescended testicle were infertile, compared with 5% of men who had normal testes. Even one undescended testicle may impair fertility. In cryptorchidism, the testes are exposed to the higher internal body heat, but this may not totally explain the damage in sperm production that can occur. (Men who suffer from this condition should be aware that even if the testicle is surgically moved to the scrotum, their risk of testicular cancer is significantly increased, warranting careful self-exams and regular follow-up with a doctor.)
• Hypospadias. This is a birth defect in which the urinary opening is on the underside of the penis, can prevent sperm from reaching the cervix if not surgically corrected.

Click the icon to see an image of an undescended testicle.

Click the icon to see an image of hypospadias.

Blockage in the Tubes that Transport Sperm. Some men are born with a blockage in the epididymis or ejaculatory ducts or other problems that later affect fertility. One center reported that 2% of men seeking treatment had no vas deferens.

Anorchia. In the very rare condition known as anorchia, a man is born without any testes.

Syringomyelia. This is a disease of the spinal cord that results in no ejaculate at all (aspermia).

Cancer and Its Treatments

Birth rates among cancer survivors are only 40 - 85% of normal rates. Certain cancers, particularly testicular cancer, impair sperm production, often severely. Cancer treatments such as chemotherapy and radiation can damage sperm quality and quantity, causing infertility. The closer radiation treatments are to reproductive organs, the higher the risk for infertility. Fortunately, while men may fail to produce sperm for as long as 5 years after radiation therapy, many men eventually recover their sperm production ability. Chemotherapy with drugs that harm reproductive function tends to affect fertility more severely in men than in women. New drug regimens are helping to improve fertility rates.

Adolescents and adult men undergoing cancer treatments who may want to father children should consider banking and freezing their sperm for later use in assisted reproductive therapies. This technique is called sperm cryopreservation. Sperm cryopreservation is recommended by the American Society of Clinical Oncology as the method with the highest likelihood of success for male cancer survivors. However, these banking methods are not appropriate for pre-adolescent boys being treated for childhood cancers such as leukemia. Researchers are investigating ways that stem cell transplantation may someday help these children regain their fertility while avoiding leukemia relapse.

Infections

There is some controversy over the effect of infections on infertility. Simply detecting the presence of an infection in infertile men does not necessarily mean that it has any relationship to the infertility itself. Some experts believe that the immune response to some infections may release inflammatory factors and oxidants, chemically unstable particles that can damage sperm. The exact impact of this process on sperm is unclear, however. Infections may alter the liquidity of semen and sperm motility, although these are likely to be temporary effects. Among the infections most implicated in infertility are:

Sexually Transmitted Diseases. Repeated Chlamydia trachomatis or gonorrhea infections are most often associated with male infertility. Such infections can cause scarring and block sperm passage. Human papillomaviruses, the cause of genital warts, may also impair sperm function.

Mycoplasma. Mycoplasma is an infectious organism that appears to fasten itself to sperm cells and render them less motile.

Mumps. When mumps develops after puberty, it damages the testicles in 25% of men afflicted with the disease. (Interferon, an anti-viral drug, may help prevent infertility in adult males with active mumps, but the drug is highly toxic and caution is essential.)

Glandular Infections in the Urinary Tract or Genitals. Glandular infections that may affect fertility include prostatitis (in the prostate gland), orchitis (in the testicle), semino-vesculitis (in the glands that produce semen), or urethritis (in the urethra), perhaps by altering sperm motility. Even after successful antibiotic treatment, infections in the testes may leave scar tissue that blocks the epididymis.

Other Conditions Associated with Infertility

Medical Conditions. Other medical conditions that can affect male fertility include any severe injury or major surgery, diabetes, HIV, thyroid disease, Cushing syndrome, heart attack, liver or kidney failure, and chronic anemia.

Medications

The effects of medications on sperm quality and count have not been rigorously studied, and many medicines are commonly prescribed without knowing whether they impair fertility. Anabolic steroids (which are often abused by weight lifters and other athletes) deserve special notice because they are known to severely impair sperm production. Among the other drugs that can affect male fertility are cimetidine (Tagamet), sulfasalazine (Azulfidine), salazopyrine, colchicine, methadone, methotrexate (Folex), phenytoin (Dilantin), corticosteroids, spironolactone (Aldactone), thioridazine (Mellaril), and calcium channel blockers.

Diagnosis

In any fertility work-up, both male and female partners are tested if pregnancy fails to occur after a year of regular unprotected sexual intercourse. It should be done earlier if a woman is over age 35 or if either partner has known risk factors for infertility. A work-up can not only uncover the causes of infertility but also detect other potentially serious medical problems as well, including genetic mutations, cancer, or diabetes.

Fertility History

The patients will provide the doctor with a detailed history of any medical or sexual factors that might affect fertility:

• Frequency and timing of sexual intercourse
• Duration of infertility and any previous fertility events
• Childhood illnesses and any problems in development
• Any serious illness (diabetes, respiratory infections, cancer, previous surgeries)
• Sexual history, including any sexually transmitted diseases
• Any exposure to toxins, such as chemicals or radiation
• History of any medications and allergies
• Any family history of reproductive problems

Physical Exam

A fertility specialist, usually a urologist, will perform a physical examination. A physical examination of the scrotum, including the testes, is essential for any male fertility work-up. It is useful for detecting large varicoceles, undescended testes, absence of vas deferens, cysts, or other physical abnormalities.

• Varicoceles large enough to possibly interfere with fertility can be felt during examination of the scrotum. In such cases, they are described as feeling like "a bag of worms." They disappear or are greatly reduced when the patient lies down, so the patient should be examined for varicocele while standing.
• Checking the size of the testicles is helpful. Smaller-sized and softer testicles along with tests that show low sperm count are strongly associated with problems in sperm formation. Normal testicles accompanied by a low sperm count, however, suggest possible obstruction. The doctor may also take the temperature of the scrotum with a test called scrotal thermography.
• The doctor will also check the prostate gland for abnormalities.
• The penis is checked for warts, discharge from the urinary tract, and hypospadias (incorrect location of the urethra opening).

Post-Ejaculatory Urine Sample

A urine sample to detect sperm after ejaculation may rule out or indicate retrograde ejaculation. It also may be used to test for infections.

Semen Analysis

The basic test to evaluate a man's fertility is a semen analysis. The sperm collection test for men who can produce semen involves the following steps:

• A man should abstain from ejaculation for several days before the test because each ejaculation can reduce the number of sperm by as much as a third. (The maximum number of sperm is usually obtained by abstaining for about 4 days.)
• A man collects a sample of his semen in a collection jar during masturbation either at home or at the doctor's office. Proper collection procedure is important, since the highest concentration of sperm is contained in the initial portion of the ejaculate. Specially designed condoms may be available that will enable collection of a sample during sexual intercourse. (Regular condoms are not useful, since they often contain substances that kill sperm.)
• The sample should be kept at body temperature and delivered promptly, because if the sperm are not analyzed within 2 hours or kept reasonably warm, a large proportion may die or lose motility.
• A semen analysis should be repeated at least three times over several months.

The sperm count test is performed if a man's fertility is in question. It is helpful in determining if there is a problem in sperm production or quality of the sperm as a cause of infertility. The test may also be used after a vasectomy to make sure there are no sperm in the semen.

Both the man and the woman should be present when the doctor discusses the results of this analysis so that both partners will understand the implications. The analysis report should contain results of any abnormalities in sperm count, motility, and morphology as well as any problem in the semen. It should be noted, however, that semen analysis alone is not necessarily a definitive indicator of infertility or fertility.

Sperm Count. A low sperm count should not be viewed as a definitive diagnosis of infertility but rather as one indicator of a fertility problem. Although in a large 2001 analysis sperm counts below 13.5 million were considered a strong indication of infertility, pregnancy was possible so long as any motile sperm were present. If there are no sperm cells at all in the semen, the doctor checks for obstruction in the tubes or for Sertoli cell-only syndrome, in which there are no sperm-producing cells in the testes. An at-home test (FertilMARQ) is now available to help gauge sperm quantity.

Sperm Motility. Motility (the speed and quality of movement) is graded on a 1 to 4 ranking system. For fertility, motility should be greater than 2.

• Grade 1 sperm wriggle sluggishly and make little forward progress. (Sperm that, in fact, clump together may indicate that antibodies to the sperm are present.)
• Grade 2 sperm move forward, but they are either very slow or do not move in a straight line.
• Grade 3 sperm move in a straight line at a reasonable speed and can home in on an egg accurately.
• Grade 4 sperm are as accurate as Grade 3 sperm, but move at terrific speed.

More than 63% of sperm should be motile for normal fertility, but even men whose motile sperm constitutes only about a third of the total sperm count should not rule out conception. Testing for sperm motility is particularly valuable for predicting the success of artificial insemination and which men might be candidates for the Intracytoplasmic sperm injection (ICSI) fertilization technique, in which the sperm is inserted directly into the egg and motility plays almost no role.

Sperm Morphology. Morphology is the shape and structure of the sperm and, of the three main sperm values, may be the best predictor of fertility. Older reports indicated that about 60% of the sperm should be normal in size and shape for adequate fertility. However, a 2001 major analysis used a much broader range of criteria for sperm morphology and concluded that values over 12% were good predictors of fertility. Determining the morphology of the sperm is particularly important for the success of the fertility treatments in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI).

Seminal Fluid. The seminal fluid (semen) itself is analyzed for abnormalities. The color is checked and should be whitish-gray.

The amount of semen is important. Most men ejaculate 2.5 - 5 milliliters (mL) or cubic centimeters (cc) (1/2 - 1 teaspoon) of semen. Either significantly higher or lower amounts can be a sign of trouble:

• Amounts greater than 1 cc but lower than 2.5 cc may indicate prostate problems or frequent intercourse.
• A semen sample that is less than 1 cc could indicate a blockage of the ejaculatory ducts or other tubular abnormalities.
• No ejaculate at all may signal retrograde ejaculation.
• High amounts of ejaculate may, in some cases, also contribute to infertility.

The semen will be tested for how liquid it is. (Normal semen is liquefied within 20 minutes after adding certain enzymes.) Abnormal results suggest the following:

• Overly sticky fluid suggests problems in the prostate gland (which adds fluid to sperm)
• Overly watery fluid suggests lack of sperm

The amount of sugar (fructose) in sperm will be measured:

• Since fructose is added to the semen in the epididymis, an absence of fructose indicates that an obstruction has occurred either in the vas deferens or the epididymis.
• Conversely, if there is fructose in the semen but no sperm, then the channel from the epididymis is open but there is a defect in sperm production.

Other factors may also be measured:

• White blood cell counts are taken to detect infection.
• Low levels of a substance called inhibin B, which appears to be produced only in the testes, may indicate blockage or other defects in the seminiferous tubules.
• Low levels of another compound, alpha-glucosidase, may also indicate blockage in the epididymis.

Blood Tests

Blood tests are used for measuring several factors that might affect fertility:

Hormonal Levels. Tests for certain hormone levels are indicated if semen analysis is abnormal (especially if sperm concentration is less than 10 million per milliliter) or there are other indications of hormonal disorders.

• Blood tests for testosterone and follicle-stimulating hormone (FSH) levels are usually taken first.
• If testosterone levels are low, then luteinizing hormone (LH) are measured.

Low levels of FSH, LH, and testosterone indicate a diagnosis of hypogonadotropic hypogonadism. Very high FSH levels with normal levels of other hormones indicate abnormalities in initial sperm production. Usually this occurs only if the testicles are severely defective, causing Sertoli cell-only syndrome, in which sperm-manufacturing cells are absent. Other hormones, such as prolactin, estrogen, or stress hormones may be measured if there are symptoms of other problems, such as low sexual drive or the presence of breasts.

Infections. Blood tests can also determine the presence of any infections that might affect fertility, including HIV, hepatitis, and Chlamydia.

Postcoital Test

The postcoital test, also known as the cervical mucus penetration test, is designed to evaluate the effect of a woman's cervical mucus on a man's sperm. Typically, a woman is asked to come into the doctor's office within 2 - 24 hours after intercourse at mid-cycle (when ovulation should occur). A small sample of her cervical mucus is examined under a microscope. If the doctor observes no surviving sperm or no sperm at all, the cervical mucus should then be cultured for the presence of infection. The test cannot evaluate sperm movement from the cervix into the fallopian tubes or the sperm's ability to fertilize an egg.

Sperm Antibodies

If a man has had a vasectomy reversed and still cannot conceive or if semen analysis shows sperm clumping together, blood tests for anti-sperm antibodies will be conducted. Anti-sperm antibodies may also develop after genital infection or injury to the testes. The primary negative effect of these antibodies is to bind the sperm to the woman's cervical mucus, preventing the sperm from swimming further up.

Testicle Biopsy

Occasionally, a testicle biopsy may be performed, particularly for the following:

• If Sertoli cell-only syndrome is suspected, in which sperm-producing cells in the testes are absent. It should be noted that specific cellular patterns can determine whether this condition is congenital (inborn) or caused by some later injury. This distinction is important in predicting the potential success of later sperm retrieval procedures.
• For detecting obstruction in the transport system when sperm production looks normal but the count is low.

The standard biopsy procedure requires incisions (called an open approach) under anesthesia. It can be painful afterward. More than one biopsy may be needed in the case of suspected Sertoli cell-only syndrome, since one area may not have cell-producing cells, but other regions may contain normal sperm. Biopsies of both testes are more accurate than one. (Doctors must be careful to avoid the epididymis during a biopsy, since it is a continuous tiny tube and would be destroyed.) Patients may consider freezing any sperm retrieved during biopsy for later use.

Ultrasound

Ultrasound imaging may be used to accurately determine the size of the testes or to detect cysts, tumors, abnormal blood flow, or varicoceles that are too small for physical detection (although such small veins may have little or no effect on fertility). It also can detect testicular cancer, which some experts believe make it worthwhile as a routine procedure for any male infertility work-up.

Click the icon to see an image of testicular ultrasound.

Genetic Testing

Genetic testing may be warranted in men who are severely deficient in sperm and who show no evidence of obstruction, particularly in men undergoing the ICSI procedure. One study of men attending a fertility clinic showed that a third had genetic defects. If genetic abnormalities are suspected in either partner, counseling is recommended. Researchers are testing techniques such as preimplantation genetic diagnosis (PGD) that can examine all the chromosomes in a human embryo and detect defective genes, such as those for cystic fibrosis, at the very earliest stages. If it proves useful, it may help identify numerous abnormalities that increase the risk for infertility, treatment failures, or genetic defects in the offspring. In fact, a 2003 study suggested that performing an initial genetic analysis to determine DNA fragmentation in sperm may be a better way of predicting whether conception will succeed than analyzing semen.

Fertilization Tests

In men who wish to undergo fertility treatments, certain tests will help determine the right strategies.

The Hamster Test. The hamster test, or micro-penetration assay test, uses the sperm sample to fertilize hamster eggs that have had their covering removed to allow penetration. If less than 5 - 20% of the eggs are fertilized, infertility is diagnosed. It may be useful for determining the best assisted reproductive treatment options for men with infertility.

The Human Zona Penetration Test. The human zona penetration test uses sperm to fertilize dead human eggs, which are usually obtained from an ovary that was removed for medical purposes. (Like the hamster test, the procedure cannot result in a living embryo.) Results may provide the same information as the hamster test and also indicate whether the sperm can penetrate the outer coating of an egg.

Acrosome Reaction Test. Tests that induce the ability of the sperm's enzyme-rich covering (acrosome) to dissolve can be very useful.

Other Tests. Additional advanced laboratory tests to measure sperm function, such as computer-aided sperm motility analysis, may also be performed. Some of these tests assess such factors as level of cell-damaging oxidants.

Treatment

Many men diagnosed with infertility in the past would be considered treatable now, even some men with spinal cord injuries. Unless a man produces no sperm at all, recent developments in treatment have made fertility possible for many men willing to undergo treatment and bear the expense. Before undergoing more advanced procedures, most couples trying to conceive should attempt some simple lifestyle changes.

Timing and Monitoring Sexual Activity for Best Results

Both male and female hormone levels fluctuate according to the time of day, and they also vary from day to day and month to month. Some timing tips might be helpful.

Male Hormone Levels and Sexual Activity. Male hormone levels are highest in the morning. In one study of men, their sexual activity was highest in October, when conception rates were also high.

Fertility and Seasonal Changes. Different studies have reported higher sperm counts in the winter than in the summer. For women, fertility rates as measured by treatment success are highest in months when days are longest.

Monitoring Basal Body Temperature. To determine the most likely time of ovulation and therefore the time of fertility, a woman is instructed to take her body temperature, called her basal body temperature. This is the body's temperature as it rises and falls in accord with hormonal fluctuations.

By studying the temperature patterns after a few months, couples can begin to anticipate ovulation and plan their sexual activity accordingly. Couples must try to avoid becoming fixated on the chart, however, in scheduling their sexual activity. Spontaneity can be lost, and the stress on the relationship can be quite severe.

Hormone Monitoring Systems for Women. A device called a saliva fertility monitor (Fertility Tracker) uses a microscope to view slides containing saliva and monitors estrogen levels. Home test kits that monitor reproductive hormone levels in the urine are also available. They are less costly than the saliva test but are messier. Monitoring hormone levels helps to determine when a woman is ovulating.

Frequency of Intercourse. The question of how often a couple should have intercourse is in debate. Some experts say that having sex more than 2 days a week adds no benefits. And, in fact, frequent sexual activity lowers sperm count per ejaculation. Some studies have indicated, however, that having intercourse every day, or even several times a day, before and during ovulation, improves pregnancy rates. Although sperm count per ejaculation is low, a constantly replenished semen supply is more likely to result in a fertilized egg.

Dietary Considerations

Everyone should eat a healthy diet rich in fresh fruits, vegetables, and whole grains. Replace animal fats with monounsaturated oils, such as olive oil. Fish is also a good choice, and fish oils may have benefits for men with infertility. Certain specific nutrients, vitamins and minerals may also improve fertility.

• Higher antioxidant intakes of vitamin C, vitamin E, and beta-carotene may help improve sperm numbers and motility, according to a 2005 study. The study included both food and supplement sources.
• Vitamins C and E may also help repair DNA damage to sperm. According to a 2005 study, men who took 1 gram per day of these vitamins significantly reduced their percentage of DNA sperm fragmentation within 2 months.
• A 2002 study found that infertile men who took zinc (66 mg) and folic acid (5 mg) supplements daily for 6 months increased their sperm counts by 74%. However, a 2005 study found that zinc and folate did not affect sperm quality.
• The dietary supplements L-carnitine and L-acetylcarnitine may help improve sperm motility, according to several recent clinical trials.

Other Lifestyle Changes

A man who wants to increase his sperm count should also pursue a healthy lifestyle.

• Avoid cigarettes and any drugs that may affect sperm count or reduce sexual function.
• Overweight men should try to reduce their weight.
• Get sufficient rest, and exercise moderately but regularly. (Those who exercise excessively might cut back, but not stop altogether.)
• Stress may contribute to reduced sperm quality. It is not known if stress reduction techniques can improve fertility, but they may help couples endure the difficult processes involved in fertility treatments.
• Although studies now indicate that tight underwear and pants pose no threat to male fertility, there is no harm in wearing looser clothing.
• To prevent overheating of the testes, men should avoid hot baths, showers, and steam rooms.

Planning for Stress and Depression

The fertility process is a roller coaster of emotions that are present throughout both failure and success. There are almost no sure ways to predict which couples will eventually conceive. Some couples with multiple problems will overcome great odds, while other seemingly fertile couples fail to conceive. Many of the new treatments are remarkable, but a live birth is never guaranteed. The emotional burden on the couple is considerable, and some planning is helpful.

Planning for Emotional Turmoil.

• Decide in advance how many and what kind of procedures will be emotionally and financially acceptable and attempt to determine a final limit. Fertility treatments are expensive.
• Determine alternatives (adoption, donor sperm or egg, or having no children) as early as possible in the fertility process. This can reduce anxiety during treatments and feelings of hopelessness in case conception does not occur.

Managing Emotional Stress During the Process. Managing negative emotions in both men and women can be viewed as important as medical treatment. The process of fertility evaluation can be very difficult for many men. In a 2003 study, over 10% of men who required a second semen sample were unable to collect a semen sample using masturbation. Such men had had no problems with a first collection, but after being asked for additional samples they suffered severe anxiety during both masturbation in the fertility clinic and during regular sexual activity at home. Numerous studies reported a significant association between psychologic factors, particularly anxiety, and fertility treatment failure in women.

Managing the Emotional Effects of the Outcome. After enduring the process of fertility evaluation, the couple must face the outcome, and even a positive outcome has emotional repercussions.

• Effects of Failure. Needless to say, the emotional stress of failure can be devastating even on the most loving and affectionate relationships and even in those who have prepared for the possibility of failure. Neither the male nor female partner should hesitate to seek professional help if the emotional burdens are too heavy.
• Effects of Genetic Testing. As advanced technologies allow testing and greater genetic information at the earliest stage, potential parents will have to learn to deal with the uncertainties of possible chromosomal abnormalities, which may or may not be significant.
• Effects of Multiple Births. A successful pregnancy that results in a multiple birth introduces new complexities and emotional problems. One study reported a very high rate of depression in women with triplets, particularly if they had little help from others, and especially if their husbands weren't involved.
• Effects on Parenting. Once the fertility treatment-assisted child arrives, parents (both men and women) are more likely to be anxious and to have less confidence than those who conceive naturally.

Assisted Reproductive Technologies

Assisted reproductive technologies (ART) are medical techniques that help couples conceive. These procedures involve either:

• A couple’s own eggs or sperm
• Donor eggs, sperm, or embryos

Fertilization may occur either in the laboratory or in the uterus. In the U.S., the number of live birth deliveries from ART increased by 128% from 1996 - 2002. More than 45,000 babies are now born in the U.S. each year using assisted reproductive technologies.

ART includes fertility drug treatments, artificial insemination (AI), in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and other procedures.

Choosing a Fertility Clinic

Choosing a good fertility clinic is important. The government does not always regulate centers offering assisted reproductive techniques, and abuses have been reported, including lack of informed consent, unauthorized use of embryos, and failure to routinely screen donors for disease.

The clinic should always provide the following information:

• The live-birth rate (not just pregnancy success rate) for other couples with similar infertility problems. (Multiple births, such as twins or triplets, are counted as one live birth.)
• Such statistics should include high-risk women, such as those who are older or fail to produce eggs. (Some disreputable clinics give success percentages that exclude high-risk women from their total, thereby making the percentage of success much higher.)

Advanced fertility procedures and medications are extremely expensive and often not covered by insurance. Couples should be cautious about offers of rebates in the event of failure. The clinics offering them are often significantly more expensive than those that don't.

Artificial Insemination

Artificial insemination (AI) it is the least complex of the assisted reproductive technologies and is often tried first in uncomplicated cases of infertility. AI either involves placing the sperm directly in the cervix (called intracervical insemination) or into the uterus (called intrauterine insemination, or IUI). IUI is the standard AI procedure.

It is useful under the following circumstances:

• When the woman's cervical mucus is unreceptive.
• When donor sperm are required.
• If the man's sperm count is very low (although it is preferable if at least 5 million per milliliter are motile).
• When unexplained infertility exists in both partners.

Those in whom AI fails, couples with specific fertility defects, or older women may be candidates for more advanced reproductive technologies.

Pregnancy Rates. A review of 45 studies reported that in unexplained infertility cases, the per-cycle pregnancy rates were 4% for intrauterine insemination (IUI) alone and 8 - 17% per cycle for IUI combined with superovulation, a procedure that uses fertility drugs to bolster egg recovery.

Researchers in 2002 study suggested IUI as a reasonable first option for many women under age 43. It is less expensive and poses less risk for multiple births than the more advanced assisted reproductive technologies (ART), such as in vitro fertilization. Although IVF procedures are more effective per cycle, couples tend to be able to afford more IUI cycles, so the pregnancy rates over time are very similar.

The Artificial Insemination Procedure. The AI procedure is as follows:

• A woman usually (but not always) takes fertility drugs in advance.
• The man must produce sperm at the time the woman is ovulating.
• The sperm are subjected to certain so-called "washing" procedures. They are then inserted into the uterine cavity through a long, thin catheter.

The administration of fertility drugs and sperm retrieval is timed so that the process can coincide with time of ovulation. A 2000 study suggested that women who lay quietly for 10 minutes after sperm were implanted had a significantly higher rate of pregnancy than those who got up immediately.

Intracytoplasmic Sperm Injection (ICSI)

Intracytoplasmic sperm injection (ICSI) is an assisted reproductive technology used for couples when male infertility is the main factor. It involves injecting a single sperm into an egg obtained from in vitro fertilization (IVF). The procedure is very simple:

• A tiny glass tube (called a holding pipet) stabilizes the egg.
• A second glass tube (called the injection pipet) is employed to penetrate the egg's membrane and deposit a single sperm into the egg.
• The egg is released into a drop of cultured medium.
• If fertilized, the egg is allowed to develop for 1 - 2 days and then is either frozen or implanted.

The greatest concern with this procedure has been whether it increases the risk for birth defects. However, studies in 2002 and 2003 reported no higher risks of birth defects in children born using ICSI procedures. While some studies have shown a higher number of birth defects in children conceived with ICSI, experts think that this may have more to do with the genetic background of the parents than ICSI itself. Recent research suggests that ICSI children develop normally. A 2006 study of 8-year-old children conceived with ICSI found no important differences between these children and children who were conceived naturally.

In Vitro Fertilization (IVF)

About 71% of ART procedures now use in vitro fertilization (IVF) with the woman's own eggs. An in vitro procedure is one that is performed in the laboratory. Advances in these procedures have dramatically increased the rate of live births.

The best candidates for IVF are women with damaged fallopian tubes, and some experts believe it is a better option than attempting surgical repair. IVF is also used when infertility is unexplained or when the male partner has the infertility problem. A typical IVF procedure is as follows:

• The doctor first induces superovulation using fertility drugs so that several eggs can be harvested from the ovary before they have been released from the follicles. Higher doses of fertility drugs for subsequent cycles do not appear to add any advantage in women who have a poor response the first time.
• To harvest eggs, the doctor generally inserts a probe into the vagina and is guided by ultrasound. A needle is then used to drain the liquid from the follicles, and several eggs are retrieved.
• The eggs and sperm are combined in a Petri dish. Between 48 - 72 hours later the eggs are fertilized.
• The resulting embryos (the first stage toward the development of the fetus) are reimplanted into the woman's uterus.
• It takes about 2 weeks to determine if the process is successful.

IVF success rates for the first three cycles of treatment are about equal. They then decline modestly for the fourth cycle and drop significantly after the fifth cycle.

Gamete/Zygote Intrafallopian Transfer. Gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT) are adaptations of IVF. GIFT and ZIFT are used in unexplained female infertility and in mild male infertility. The success rates are similar to those of IVF, but a woman must have at least one functioning fallopian tube.

GIFT: The procedure is as follows:

• The eggs are harvested as in IVF.
• They are mixed with the sperm but not actively fertilized.
• They are immediately injected back into the woman. Laparoscopy, a technique that employs a miniature viewing device, is used with this procedure to guide the placement of the embryos or egg through a long, thin catheter into the fallopian tubes.
• The sperm and egg are placed exactly where they would be in natural fertilization.

ZIFT: The procedure is as follows.

• The eggs are harvested as in IVF.
• They are then mixed with the sperm and, in this case, are fertilized in the laboratory.
• They are then implanted in the fallopian tubes as in GIFT. (The advantage of this procedure over GIFT is that the doctor and couple are assured that fertilization has taken place and the eggs can be examined for defects before implantation.)

Success Rates for IVF Procedures

Success rates have increased in all age groups (although they are still considerably lower in older than in younger women). Chances for ART success are also greater among women who do not have uterine abnormalities and have had previous successful pregnancies.

Success rates are also higher or lower depending on whether the woman uses her own eggs or whether they are donated and also whether the eggs are fresh or frozen. The highest live birth rates are with donated fresh eggs (an average of 50% per transfer) and the lowest rates are when a woman uses her own frozen eggs (an average of 29% per transfer). However, using frozen eggs is less expensive than fresh eggs, so a couple may be able to afford more cycles with frozen eggs.

Use of Donor Eggs. Older women are more likely to use donor eggs. In a 2002 study, success rates were the same for women who used donors with an age range of 20 - 40. There were also no differences in delivery rates for recipients up to age 45. Women over age 45, however, increasingly had problems with implantation, pregnancy, and delivery.

Use of Frozen Eggs. Frozen eggs tend to have lower success rates because of toxins released by cells damaged in the freezing and thawing tissues.

Other ART Techniques

In Vitro Maturation. A new technique called in vitro maturation allows fertilization without the use of fertility drugs. In this process, follicles are harvested a few days before ovulation. In such cases, up to 50 have already begun to mature. About 15 of these maturing follicles can be removed, out of which 2 or 3 can produce healthy embryos.

Blastocyst Transfer. Blastocyst transfer is very promising. Instead of implanting the standard 2- or 3-day-old embryos in the uterus, the procedure implants blastocysts, which are more complex, 5-day-old embryos. Fewer blastocysts than embryos need to be implanted, reducing the risk for multiple births. (There is, however, a higher risk for identical twins compared to other procedures.) Offspring may be more likely to be males than females. Pregnancy rates are about 36% with a first attempt but then drop significantly. The procedure is more likely to be successful in younger than older women.

Ooplasmic Transfer. Ooplasmic transfer is a controversial experimental procedure that uses the woman's own egg and a female donor's egg and the male sperm for fertilization. Genetic material from the donor's egg plus the sperm are added to the woman's own egg. This has been successful in a few cases, but studies are very early and long-term effects are unknown. Research on this and similar procedures are currently conducted outside the United States.

Complications of ART

Since ART procedures have become more widespread since 1980, multiple births have significantly increased. About 35% of all ART births are multiple ones, with 4.3% being triplets or more. Multiple births increase the risk of complications, for both the mother and the child.

Risks to the Woman

ART, and multiple births, increase the risks for pregnancy complications. According to a 2005 study, the type of complications may depend on the infertility treatment:

• Fertility drugs. Increase risks of the placenta becoming detached from the uterus (“placental abruption”), third trimester miscarriage, and gestational diabetes.
• IVF. Increase risks of placental abruption, the placenta developing in the lower section of the uterus (“placenta previa”), dangerously high blood pressure during pregnancy (“pre-eclampsia”), and Caesarean sections.

Multiple births can also increase the risk of pregnancy death. A 2006 study indicated that women who carry multiple fetuses have a 3.6 times greater risk of dying from pregnancy complications than women with singleton pregnancies. The leading causes of death were blood clot (embolism), high blood pressure complications, excessive bleeding (hemorrhage), and infections.

Risk for Birth and Genetic Defects in Children

The main risks for children conceived with ART are complications associated with pregnancy problems and multiple births. Children conceived with ART are more likely to be born premature and to have extremely low birth weight. These conditions increase the risk for heart and lung problems, as well as learning and developmental disabilities. Premature delivery is also associated with cerebral palsy, a brain injury condition that affects muscle coordination. A 2006 study indicated that children born after in vitro fertilization have an increased risk for cerebral palsy.

However, unlike earlier research, recent studies suggest that ART does not increase the risk for chromosomal damage or other major birth defects. However, couples undergoing ART may have other factors, such as older age or genetic predispositions, which make complications more likely. Still, ART remains a good option for many infertile couples. The likelihood of having a healthy single child of normal birth weight using ART is about 94%. The likelihood of having a child free of major birth defects is about 91%. Frozen eggs do not appear to pose any higher risk for developmental problems.

Preimplantation genetic diagnosis (PGD) is now available in a few fertility centers. It can help identify genetic defects in the offspring and may help parents determine future problems. Such testing, however, also raises significant emotional issues that should be addressed beforehand.

Limiting Birth Numbers

Given the hazards of multiple births, parents must make some hard decisions if the treatment produces multiple embryos. The choices are limited:

• Carry all of them to term, which increases health risks for both the mother and the developing fetuses
• Complete abortion
• Embryo reduction, in which the doctor removes one or more embryos (possibly endangering the remaining embryos)

At this time, the best approach is to limit the number of implanted embryos in the first place. Experts are attempting to develop methods to reduce the risk for multiple births:

• Most centers now implant two to three embryos at a time, and the remainder can be frozen for future use. (Frozen eggs do not appear to pose a risk for developmental problems in children conceived using them.) This limits the chance for success, but implanting more than three embryos only increases success rates very slightly, whereas the risk for multiple births increases significantly.
• Reducing the dosage of fertility drugs also reduces the risk for multiple births, but not significantly and it too reduces the chance for successful outcome.
• Blastocyst transfer may help reduce the chances for multiple births.

Other Treatments

Hormone therapy has been effective for women with infertility problems, but has been disappointing in men except in a few specific cases:

• Gonadotropin-releasing hormone (GnRH) is often very helpful in restoring fertility in men with gonadotropin deficiency and hypogonadism.
• GnRH may be useful for restoring sperm production after chemotherapy treatments.
• Sperm production occasionally responds to low doses of estrogen and testosterone or testosterone alone, menotropins (Pergonal, Repronal), clomiphene citrate (Clomid), human chorionic gonadotropin (hCG), or human follicle-stimulating hormone (r-hFSH, Gonal-F).
• Prolonged treatment with follicle-stimulating hormone (FSH) prior to ICSI may improve implantation rates.
• Aromatase inhibitors block aromatase, an enzyme that is a major source of estrogen in many major body tissues. These drugs include anastrozole (Arimidex) and letrozole. (Femara). They may be helpful for specific men whose infertility is associated with an abnormal testosterone-to-estrogen ratios.

Nonhormonal Drugs

Bromocriptine. Bromocriptine (Parlodel) is used in men whose infertility is related to excess prolactin manufactured by the pituitary.

Antibiotics. Infections interfering with fertility may be successfully treated with antibiotics.

Mast Cell Blocking Antihistamines. Studies report that certain antihistamines that block mast cells may be beneficial for some men with low sperm counts. Mast cells are inflammatory immune factors that may play a role in lower sperm quality. Studies have reported that two such drugs used overseas, ebastine and tranilast, improved pregnancy rates. Similar antihistamines in the U.S. are fexofenadine (Allegra), loratadine (Claritin), and cetirizine (Zyrtec).

Varicocele Repair

Repair of a varicocele (varicocelectomy) in men with infertility problems is a common surgical practice. Nevertheless, although many urologists favor varicocele repair, the few well-conducted studies on this procedure suggest that it does not improve the chances for a successful pregnancy. Some experts argue that such studies were not using the most advanced techniques, which may be more effective. Some studies report that repair may improve the success rate of assisted reproductive technologies, such as intrauterine insemination (IUI). Still, the overall benefits remain uncertain, and additional rigorous trials are needed. In any case, the procedure does not appear to be beneficial for improving fertility in men whose varicoceles are very small.

Varicocele repair for fertility is sometimes considered when the following conditions are met:

• When the varicocele can be felt during a physical examination.
• Surgical treatment of varicoceles may be important in boys and adolescents to prevent later testicular damage.
• When the male partner with varicoceles has abnormal semen quality or abnormal sperm function test results.
• When the couple has known infertility, and the man has varicoceles but the woman is either fertile or can be treated for her infertility.

Varicocelectomy. Varicocelectomy, the standard repair procedure, involves tying off the swollen and twisted veins. Recovery takes 6 days, and most men cannot resume full activity for about 3 weeks. This technique eliminates 90% of varicoceles.

Recent surgical techniques use laparoscopy, which only requires tiny incisions (less than an inch). This approach allows for quicker recovery, although the procedure itself takes longer. It also has a higher rate of complications than the standard approach.

Varicocele Embolization.A nonsurgical technique called varicocele embolization may eventually prove to be an effective and less painful treatment for varicoceles, including those in young boys. It involves inserting a narrow tube (catheter) through a small incision in the neck or leg. Tiny steel plugs are passed through the catheter to block off the affected veins. It takes 15 - 45 minutes under local anesthetic. Recurrence occurs in more than 10% of cases, often requiring conventional surgery. This procedure is not yet widely available, and it may not be appropriate for some men.

Treatment for Retrograde Ejaculation and Failure of Emission

Men with retrograde ejaculation and failure of emission caused by surgery, severe disease, or spinal cord injury are treated with various methods.

• Drugs known as alpha-adrenergic agonists, including pseudoephedrine (Sudafed, Actifed), stimulate muscle contraction and help ejaculation. The tricyclic antidepressant imipramine (Tofranil) has similar effects, and in one analysis of 35 studies was more effective than pseudoephedrine. Promising investigational drugs include amezinium, which increases blood pressure.
• If drugs are not effective, a technique called electrovibration (or electrical stimulation) is often beneficial. (Drugs in any case are not helpful for men with complete failure of emission.)

With any of these methods, the sperm can be collected for intrauterine insemination or assisted reproductive techniques. Spontaneous conception is possible, but not common, even with these treatments.

To prepare sperm for IVF, men with retrograde ejaculation typically use sodium bicarbonate four times a day to reduce the acidity of the urine. After ejaculation, the man urinates or has a catheter (a tube) inserted to withdraw urine, which is then submitted for washing techniques to separate out the sperm.

Techniques for Men with Spinal Cord Injury

Procedures that assist ejaculation are helping men with spinal cord injury conceive children. Vibratory or electronic stimulation is proving to be very beneficial for many of these men. The sperm retrieved using these methods are inserted into the women using self-insemination, IUI, IVI, or ICSI. Nearly a third of couples achieve pregnancy, a success rate that approaches natural conception.

Vasectomy Reversal (Vasovasostomy)

Vasovasostomy. For men who wish to conceive after vasectomy, reversal surgery (vasovasostomy) may restore fertility. In vasovasostomy the severed ends of the vas deferens (which were cut during vasectomy) are reconnected to reestablish the flow of sperm. The reversal procedure is difficult. It involves sewing together the two ends of both tubes, each with pinhead sized openings. [For more information, see In-Depth Report #37: Vasectomy and vasovasotomy.]

Pregnancy Rates After Vasovasostomy. An Australian study reported that pregnancy rates in the late 1990s after reversal surgery were nearly four times higher than they were in the early 1980s. Pregnancy rates of over 50% are now being reported after a vasovasostomy. One study indicated that when successful conception occurs, it does at an average of 1 year after the surgery.

A successful reversal is more likely if the following conditions are present:

• The section removed during vasectomy was not long
• The original procedure was performed on straight sections of the vas deferens
• The pieces joined during the vasovasostomy are of equal size

The closer in time the vasovasostomy is to the original vasectomy, the better. In one large study, the pregnancy rates were 76% for those who had vasectomy less than 3 years before reversal surgery, but decreased to 30% for those men who had a vasectomy more than 15 years earlier. The decrease in rates as time goes by is probably due to an increase in the chance for obstruction of the epididymis and the development of anti-sperm antibodies. Success rates, according to some studies, are slightly better if the male partner does not change female partners after the procedure. Other studies suggest that it makes no difference if the man has a new female partner. The age of the woman is an important factor, and the chances of achieving pregnancy are best for women younger than age 35. Some research suggests that men who have a vasectomy reversal may have a greater rate of sperm chromosomal abnormalities than normal fertile men.

Reversal versus ART. Even though newer techniques such as ICSI are improving pregnancy rates after vasectomy, vasovasostomy is still a better choice than assisted reproductive technologies (ART) for most men who want children.

Success rates with reversal surgeries are improving, and the costs are lower than with ART. In addition, a vasovasostomy does not pose a risk for multiple births. In one study, the pregnancy rate for vasovasostomy was 52%, whereas success after intracytoplasmic sperm injection (ICSI) was between 25 - 30% (ICSI is the ART treatment of choice for men who have had vasectomy). Even for men who have failed vasovasostomy, a repeat procedure appears to be less expensive than embarking on fertility treatments at that time.

ART may, however, be a better approach than reversal for men with evidence of anti-sperm autoantibodies due to vasectomy. ICSI may also be more effective than reversal surgeries in men whose vasectomy was conducted at least 15 years or more beforehand.

Miscellaneous Surgical Procedures

Surgical Treatment of Obstructions. Obstructions in the area of the ejaculatory ducts have been successfully treated by excising or scraping the area where the prostate gland surrounds the urethra and by reconstructing the ducts.

Correcting Undescended Testicles. Undescended testicles of young boys may be repositioned surgically to prevent later infertility. It is important to perform the operation before 15 - 18 months of age to prevent the destruction of most of the sperm-producing cells, which occurs if the testicles remain in the abdomen.

Experimental Treatments

Stem Cells. Researchers are investigating using sperm stem cells to treat male infertility. The research is still in its earliest stages. In 2004, researchers announced that they had successfully grown sperm progenitor cells in the laboratory. These types of cells could potentially develop into sperm cells capable of fertilizing an egg. This discovery was an important first step for developing stem cell infertility treatments.

Resources

• www.resolve.org -- National Infertility Association
• www.asrm.org -- American Society for Reproductive Medicine
• www.urologyhealth.org -- American Urological Association
• www.theafa.org -- American Fertility Association
• www.ssmr.org -- Society for the Study of Male Reproduction
• www.sart.org -- Society for Assisted Reproductive Technology
• www.cdc.gov/ART/index.htm -- Centers for Disease Control: Assisted Reproductive Technology Report

References

Lee SJ, Schover LR, Partridge AH, Patrizio P, Wallace WH, Hagerty K, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol. 2006 Jun 20;24(18):2917-31.

Sallmen M, Sandler DP, Hoppin JA, Blair A, Baird DD. Reduced fertility among overweight and obese men. Epidemiology. 2006 Sep;17(5):520-3.

Wyrobek AJ, Eskenazi B, Young S, Arnheim N, Tiemann-Boege I, Jabs EW, et al. Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9601-6.

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