While the majority of couples are able to conceive after one year of protected intercourse, approximately 20% to 25% are unable to initiate a pregnancy without some form of assistance or therapy. In approximately one-third of these couples, a male factor appears to be singularly responsible, and in an additional 20% both a male and a female factor can be identified. Therefore, a male factor is at least partly responsible for difficulties in conception in roughly 50% of these couples.

Traditionally, the man's role in conception has generally been considered as simple and straightforward, but in fact, his reproductive physiology is quite complicated as it involves the secretion of multiple hormones, proper communication between the pituitary and the testes, and a series of complex steps influencing the production, maturation and delivery of healthy sperm cells that can fertilize an egg. Disruption of this complex process may result in nearly 40% of all men of reproductive age being infertile. Therefore, when a couple is having trouble conceiving both the male partner should be evaluated initially as well.

Up to half of all infertile couples present with some degree of male infertility. Male infertility ranges from measurable declines in sperm count and/or quality to the complete absence of sperm also known as azoospermia. Reproductive Endocrinologists (REI's) and other fertility specialists still consider the comprehensive semen analysis to be one of the most important initial fertility tests for the man.

	NORMAL SEMEN PARAMETERS
Volume		1.5-5.0 cc
Concentration		>20 millions per cc
Motility		>50% w/ forward motion
Morphology		=14% w/ normal forms
White Blood Cells		< 1 million per cc

LIFE Laboratories follows the criteria established by the World Health Organization (WHO). There is no absolute numerical cutoff between the values of semen analysis in men whose partners will get pregnant and those who won't; however, the results of a comprehensive semen analysis provide valuable information with regard to your very own circumstances and the best potential treatment option(s) to follow.

Whenever possible the semen analysis should be performed by a specialty laboratory with experience identifying subtle sperm/semen abnormalities. Quite often patients have to pay "out of pocket" for these tests because managed care providers typically refer them to generalist laboratories with a lower price but limited sperm testing capacity. A comprehensive semen analysis is no place to economize; the test must be performed by an Andrologist with advanced clinical laboratory training on sperm testing. Often times it is necessary to repeat the Semen Analysis or to perform additional tests on the sperm to determine long term sperm motility and survival under specifically controlled conditions (usually overnight), in addition, the sperm fertilizing ability and/or presence of antibodies or bacterial infections in the seminal fluid can also be assessed.

Interestingly, sperm require up to three months to fully develop. Therefore, a semen analysis performed today is a reflection of the conditions three months ago. The process of sperm production is very dynamic and constantly ongoing. It has been estimated that approximately 1,000 sperm cells are produced every time a man's heart beats. While new sperm are being produced by germinal cells in the testes, others down the "production line" spend about two weeks maturing in a structure outside the testes called the epididymus. During ejaculation they travel from the epididymus into the vas deferens, and out into the urethra. Blockages of these anatomical structures can lead to male infertility.

A comprehensive semen analysis provides accurate information with regard to the number of sperm normal in shape which exhibit forward progression. We call this number the total normal motile count and it's value correlates closely with pregnancy rate. To assess sperm morphology (shape) in the andrology laboratory spermatozoa are fixed with a special stain and at least 200 spermatozoa per slide are analyzed through high magnification microscopy. The criteria for a normal spermatozoon to be considered normal include a smooth, oval sperm head measuring 3-5 micrometers in length and 2-3 micrometers in width. There should be no defects of the neck, mid-piece, or tail, and a well-defined acrosome should comprise 40%-70% of the sperm head. All borderline forms are classified as abnormal. Our laboratories use the Krueger's strict morphology classification system as a routine component of the semen analysis. There is a close relationship between the number of sperm with normal shape and the fertilization rate of eggs. When the number of motile sperm is low (under 50%), a routine viability stain is also performed to determine if spermatozoa are alive and if the plasma membrane is intact. This test is based on the principle that live cells can exclude dye whereas damaged dead cells cannot.

The most common identifiable cause of infertility in men is the Varicocele, a condition in which enlarged veins in the scrotum interfere with proper temperature and hormonal regulation of the testicular tissue. These veins normally circulate blood away from the testicles thus performing a cooling function. When there is a partial vein blockage, blood circulation decreases and the temperature of the testicular tissue increases. A varicocele can usually be treated surgically by a urologist; however, fairly often surgery does not improve a man's sperm quality to a level where natural conception may occur. Before considering a varicocelectomy, a couple should be evaluated by a Reproductive Endocrinologist who can assess all female factors and determine if there is a real possibility for success in terms of achieving a naturally occurring pregnancy.

Varicoceles are found in approximately 15% of the general population, including adolescents and adults, in 35% of men with primary infertility (reported range: 19%-41%), and in 80% of men with secondary infertility. Improvements in seminal variables, testicular size, and testicular histology have been observed after surgery. Varicocele repair has been reported to improve spermatogenesis in 50%-80% of patients, and as many as 30%-40% will initiate a pregnancy after the procedure.

Sperm cells are very sensitive to "hot" and "cold" environments and must be maintained at optimal temperature. Nature has devised a unique mechanism for controlling testicular temperature with the scrotum. When the testicles become "too hot" the scrotum expands thus moving them further away from the body; by contrast, when they become "too cold" the scrotum contracts bringing the testicles closer to the body and raising the temperature. On average, the temperature of the testes is 2-3 degrees lower that the body's temperature.

Conditions that interfere with "scrotal function" and/or temperature regulation can increase the chances of male infertility. These might include tight clothing that forces the scrotum too close to the body. Some occupations that require prolonged sitting my also prevent scrotal cooling. Men attempting to initiate a pregnancy should avoid repetitive sitting in a hot tub for long periods of time.

Exposure to environmental toxins and certain medications may interfere with the production of sperm either directly or through alterations in the endocrine system. For agents such as heat, ionizing radiation, heavy metals, and some organic solvents, there are many studies that support these associations. Recent publications have also reported the effect of specific pesticides and other chemicals on testicular function. Furthermore, reversibility has been substantiated when the oligospermic (low sperm count) patient has been removed from some of these toxic environments. However, once azoospermia (no sperm present in the ejaculate) has occurred, return to a normal pre-exposure state is highly unlikely.

Lifestyle issues related to diet, smoking, excess alcohol intake, and others can also affect sperm quality. A relationship between Body Mass Index (BMI) and fertility has been clearly established in women and a similar scenario has been reported for men. In a study examining sperm parameters in 520 men with normal BMI (20-24 kg/m2), overweight BMI (25-30 kg/m2), or obese BMI (>30 kg/m2), a negative relationship between BMI and the number of normal-motile sperm cells was detected. The number of normal-motile sperm cells was highest in men with normal BMI and decreased to below normal ranges in overweight and obese men. In addition, men with BMI's over 25 kg/m2 had more sperm with chromatin damage.

Certain drugs, such as some used for the treatment of high blood pressure and cholesterol, and others such as caffeine, nicotine, alcohol, or marijuana, have also been implicated as spermatotoxic agents. Withdrawal from these substances should enable return of normal spermatogenesis if they are acting adversely. The common use of androgenic steroids by men is also a potentially significant cause of infertility. Androgenic steroids suppress normal hormonal secretion and interfere with the normal production of sperm. Obstructive Azoospermia is the second major cause of infertility in men. In this condition, a blockage or obstruction of the reproductive tract impedes the sperm cells from getting into the ejaculate. Obstructive cases of azoospermia include congenital absence of the Vas Deferens (CAVD) and/or vasectomy, a surgical procedure used for family planning purposes.

Non-obstructive Azoospermia, is another cause of male infertility in which there is no sperm in the ejaculate due to a problem with sperm production; men with Klinefelter's syndrome, Y chromosome abnormalities or idiopathic azoospermia fall into this group.

In cases of azoospermia the sperm cells need to be retrieved surgically. For example, in most cases of CAVD, Klinefelter's syndrome, failure of a vasectomy reversal, or when the man decides against a vasectomy reversal the sperm can be retrieved from the testes through a small biopsy procedure, performed under local anesthesia.

Testicular Sperm Aspiration (TESA) is an ambulatory procedure performed by the Urologist in the office very rapidly and with minor discomfort. In the laboratory we can then identify the sperm cells from a small sample of testicular tissue and using ICSI (Intracytoplasmic Sperm Injection) an isolated sperm cell is injected into each egg, giving these couples the opportunity of having children.

Microscopic Epididymal Sperm Aspiration (MESA) is a technique for the retrieval of sperm from the epididymis of men in whom transport of sperm from the testicle to the ejaculate is not possible because the drainage (ductal) system is absent or is not subject to reconstruction. This problem most commonly occurs in men with vasal agenesis, a condition in which the vas deferens or drainage system of the testicle fails to develop prior to birth. The majority of these men have mutations of the Cystic Fibrosis (CF) gene; therefore, their female partners require CF testing. In some circumstances the obstruction may be acquired after a failed epididymovasal anastomosis; here again, MESA may be indicated. While the male is being evaluated as a candidate for MESA, his wife is being screened in our IVF program where ICSI is also offered. MESA and IVF-ICSI complement each other and are an essential component of our assisted reproduction laboratories. Epididymal aspiration may be performed on the day of the wife's egg retrieval, or preferably ahead of time, and the aspirated sperm cryopreserved. The success of pregnancy from this procedure is reported to be 25%-60% depending on female factors. It is a complex process, requiring significant manipulation of the human gametes (eggs and sperm) but one that offers a previously sterile couple the chance of establishing a pregnancy using their own genetic material.

In approximately 7% of men undergoing MESA, spermatozoa retrieval is not possible. In these patients in whom the epididymal sperm reservoir is inaccessible sperm can be obtained from the testicle itself through the TESA procedure.

In some men retrograde ejaculation occurs. In these cases backward flow of semen into the bladder occurs with ejaculation. The causes of retrograde ejaculation are either anatomic, neurogenic, pharmacologic, or idiopathic. Anatomic causes include prostatectomy (open or transurethral) or bladder neck surgeries. Neurogenic causes include Spinal Cord Injury (SCI), retroperitoneal surgery, and diabetes mellitus.

The diagnosis of retrograde ejaculation is made by examination of a post-ejaculate urine (PEU). The patient is instructed to void immediately following ejaculation. A sample of the urine specimen is evaluated microscopically for sperm density and motility. Alternatively, the specimen may be centrifuged and the pellet resuspended in a special culture medium designed to maintain sperm viability.

When medical therapy fails to restore antegrade ejaculation, recovery of sperm from the bladder after ejaculation in conjunction with intrauterine insemination (IUI) or In Vitro Fertilization can be used. The male reproductive tract can also be subject to Acute or Chronic infections. Acute infections may include smallpox, mumps, sexually transmitted diseases such as Chlamydia and Gonorrhea, Epididymitis and other viral infections. Chronic infections include Tuberculosis, Leprosy and Prostatitis among others.

Other particular conditions also known for causing male infertility are Undescended Testes, a condition known as Cryptorchidism, Previous Surgery for Inguinal, Scrotal or Retroperitoneal Hernias, Major Systemic Illnesses (Especially Hepatic or Renal), Sexual Dysfunction and/or Ejaculatory Disturbances such as Retrograde Ejaculation (mentioned above) and/or various Neurological Disorders associated with Spinal Cord Injury (SCI) or disease.

Furthermore, infertility in the male can also be caused by direct or indirect injury to the testes. Examples of direct injury are testicular or pelvic trauma, heat or irradiation, whereas indirect injury can be induced by a variety of factors among which cigarette smoking, the use of recreational drugs such as Marihuana/Cocaine, the use of anabolic steroids, alcohol, certain vaginal lubricants and certain types of underwear are well known.

Advanced Sperm Tests

No single sperm test is a global indicator of male infertility. Therefore, to assess properly the ability of the spermatozoon to fertilize we may use a combination of tests. There is no widely accepted standard advanced sperm function test that is currently in use. In as many as 20% of infertile couples the diagnosis of infertility is "unexplained". In the female, this percentage is rapidly decreasing as more sophisticated techniques have been developed to accurately identify the efficacy of evaluation. In the male, we have only recently come to realize that sperm number and motility, as determined by the routine semen analysis, do not define sperm function or true sperm quality. Therefore, additional tests have been developed to identify other abnormalities of semen parameters.

The degree of DNA damage, also known as fragmentation in sperm cells can be a strong predictor of reduced male fertility. Our laboratories offer the Sperm Chromatin Structure Assay (SCSA), a test to measure the level of DNA fragmentation in sperm, and to enhance the diagnosis of and treatment for male infertility.

Sperm that appears normal by comprehensive semen analysis parameters (motile, morphologically normal sperm) may have extensive DNA damage. Sperm samples with high-levels of DNA fragmentation have a lower probability of producing a successful pregnancy.

Patients with a DNA fragmentation level of greater than 30% are likely to have significantly-reduced fertility potential, including a significant reduction in term pregnancies and a doubling of miscarriages. In a large study with in vitro fertilization (IVF) patients in which intra-cytoplasmic sperm injection (ICSI) was performed, pregnancy occurred in less than 1% of the cases when the number of sperm with damaged DNA was greater than 30%. Another study confirmed greater than 30% DFI (% sperm with damaged DNA) as a significant lack of fertility potential, 15-30% DFI as reasonable potential and less than 15% DFI as high fertility potential. Furthermore, 84% of men who fell into the "high fertility potential" category with a DFI of 15% or lower conceived within the first three months.

There are a number of factors that may help explain why a certain individual has high DNA fragmentation in the sperm, resulting in low fertility potential. When examining SCSA studies, length of sexual abstinence, age (significant increase after age 46), smoking history and exposure to high levels of air pollution all factor into significant variations in the results of this test. Sperm chromatin structure is also compromised in patients with high white blood cell counts in semen (leukocytospermia), febrile illness, or conditions such as testicular cancer. Significant exposure to prolonged heat in the testicles can also contribute to high levels of DNA fragmentation; for example, excessive hot tub time, prolongued driving times, drug use, exposure to chemicals or radiation, testicular trauma, and avid cycling are all well documented factors in affecting the SCSA results. The SCSA is not a replacement for the comprehensive semen analysis as these tests analyze different levels in the sample and should both be performed if indicated. When the results of both tests are analyzed, the patient can feel confident that he has the key information available about his chances of initiating a pregnancy naturally or through assisted reproductive technologies.

Fairly often microorganisms are present in a man's ejaculate. The presence of aerobic or anaerobic bacterial infections can also affect the quality of sperm. Although normal flora exists around the genitals, sometimes these microorganisms can cause acute or chronic infections of the sex accessory glands which are responsible for producing key components of the ejaculate.

Determining the quantitative and qualitative yield of sperm in the ejaculate is fundamental when assessing the male's reproductive potential or when undergoing assisted reproduction procedures. Often times, a semen analysis will show normal sperm parameters; however, additional tests such as the Sperm Motility Assay will determine the ability of sperm to survive and maintain motility under conditions similar to those of the womb for up to 24 hours. Despite a previous normal semen analysis, a couple may find after trying to conceive on their own for sometime that pregnancy is still elusive simply because overnight sperm survival is very low and there just aren't enough sperm available to fertilize the egg around the time of ovulation.

Sometimes a man will develop antibodies to his sperm. When this happens, the immune system miss-identifies spermatozoa as invading pathogens and attempts to destroy them. Anti-sperm antibodies usually occur as a result of testicular trauma, a vasectomy, or other situations where sperm cells or their progenitors are exposed to blood. The female partner may also develop anti-sperm antibodies. The presence of anti-sperm antibodies in semen has been correlated with lower fertilization and pregnancy rates. Several risk factors may contribute to the formation of anti-sperm antibodies, these include prior genital infections, testicular trauma or biopsy, heat-induced testicular damage, or genital tract obstructions. They can also be measured on the semen analysis when sperm agglutination or diminished motility are noticeable.

Our laboratories perform the immunobead test for the detection of anti-sperm antibodies. This test utilizes polyacrylamide beads to which rabbit antihuman antibodies have been linked. It can accurately detect IgA or IgG antibody binding to the head, midpiece, or tail of motile sperm. A finding of more than 20%-50% of sperm demonstrating immunobead binding is considered to be clinically significant. Other tests that measure antisperm antibodies in the serum or seminal plasma are less useful than sperm-bound antibody assays, as it is the sperm surface antibodies that most likely product the functional deficits associated with immunologic infertility.

Blood Tests

Laboratory investigation of testicular function begins with basic screening tests. The tests to be performed will depend on your clinical history and physical examination. The hormones most frequently measured are Testosterone (T), Luteinizing Hormone (LH), and Follicle-Stimulating Hormone (FSH).

Serum Testosterone levels in blood reflect Leydig cell function and provide an easily available indicator of testosterone production. Measurement of LH and FSH blood levels allows the physician to determine if a patient's endocrine dysfunction is the result of primary testicular failure or hypothalamic and/or pituitary deficiency.

In certain circumstances other tests are indicated. Serum prolactin might be measured in patients with signs and symptoms suggestive of a pituitary tumor, in any patient with a low serum testosterone level without an associated increase in serum LH, and in patients taking psychotropic drugs or centrally acting antihypertensives.

An assessment of other pituitary hormones (adrenocorticotropic hormone [ACTH], thyroid-stimulating hormone [TSH], and growth hormone [GH]) might be recommended in all patients with hypogonadotropic hypogonadism (LH and FSH deficiency).

Genetics and Male Infertility

Genetic abnormalities related to male infertility can be considered in terms of being (1) the cause for male infertility and (2) potentially transmissible to the offspring. Reasons for pursuing a genetic evaluation include establishing an exact diagnosis, establishing the genetic origin of the abnormality, clarifying the pattern of inheritance, and providing information on natural history, variation, and expression.Genetic abnormalities may be transmitted from either parent, or may be new, depending on the specific defect. The three most common known genetic factors related to male infertility are cystic fibrosis (CF) gene mutations leading to congenital absence of the vas deferens, Y-chromosome microdeletions leading to spermatogenic impairment, and karyotype abnormalities.

When a man has azoospermia (no sperm in the ejaculate), it is the responsibility of the physician to determine whether testicular failure or obstruction is present. If the vas deferens is not palpable, unilaterally or bilaterally, then Cystic Fibrosis gene mutation testing is necessary. The most commonly encountered condition in this category is cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations, which typically manifest in men with azoospermia and vasal or epididymal abnormalities. The most common manifestation is congenital bilateral absence of the vas deferens, which occurs in 1%-2% of men presenting with infertility. The carrier status for this autosomal recessive condition is quite common, being present in 1/25 persons of Northern European descent and with over 550 CFTR gene mutations having been reported. Because of the potentially fatal nature of this autosomal recessive disorder for the offspring, screening should be considered routine when vasal or epididymal abnormalities are suspected.

Deletions in the Y chromosome (DAZ, YSRRM, and AZF a, b, c deletions) are known to result in severe oligospermia (low sperm count) and azoospermia. Consequently, a genetic etiology of male factor infertility must be considered in these patients. It has been recommended that in patients with a sperm count of less than 10 million/mL peripheral blood be sent for Y chromosome analysis. A positive result has implications not only for diagnosis purposes, but also because of potential transmission of subfertility to a male offspring through ICSI.

Karyotyping can uncover genetic abnormalities in the infertile male including structural chromosomal disorders such as Klinefelter's (classic 47,XXY), mixed gonadal dysgenesis, chromosomal translocations, and XYY syndromes. Chromosomal abnormalities are not uncommon in the general population, as the incidence has been estimated at 0.5%. Klinefelter's syndrome is relatively common with an incidence of 1 in 500 live male births and is the most common abnormality of sexual differentiation, while the XYY male syndrome occurs in about 1 in 1000 live births. A great majority of these patients are fertile, with infertility being as common as the normal population. Identification of these disorders is important because with the advent of ICSI, men with Klinefelter's syndrome (mosaic and non-mosaic) can have sperm harvested from testis biopsies and initiate a pregnancy with resultant genetically normal embryos. Men with Klinefelter's may also have severe oligozoospermia.

Treatment Options for Male Factor Infertility

There are two basic ways to treat male factor infertility, one is pharmacologic and the other surgical. It takes two to three months for sperm to be produced and matured; in addition, there is often a six-month delay between the initiation of treatment of the man and any resulting changes in sperm parameters; therefore, the time factor with pharmacologic or hormonal treatments can be quite frustrating to a couple trying to conceive since they don't always rapidly and efficiently increase the amount of sperm.

Quite often, the benefit of hormonal therapy is largely dependent on the severity of the underlying cause of infertility in the male. By contrast, some surgical options for treatment can be quite effective. Today, procedures such as Vasectomy Reversal and ligation of varicoceles can be quite successful as long as all female factors have been thoroughly assessed by the fertility specialist.

There are very few medications that have demonstrated effectiveness in treating male infertility. If a drug is administered, it requires at least three months to show an effect, it can be very expensive, and rarely significantly improves sperm parameters. The exception to this is the male who is severely hypogonadotropic (extremely low levels of FSH and LH).

The Internet, and spam e-mail, are full of promotions for "sperm or fertility enhancers". None of these products have demonstrated clinical effectiveness and their use is a waste of money. Using today's advanced reproductive technologies it is possible for most men to create genetically related children. Intracytoplasmic sperm injection (ICSI) is an In Vitro Fertilization (IVF) in which a single sperm cell is injected directly into an egg. Currently, this procedure is very commonly used to overcome male problems.

The procedure is done using an inverted microscope using micromanipulation devices connected to microinjectors and specially made micropipettes. A holding pipette stablizes the mature oocyte (egg). From the opposite site a thin, hollow needle is pierced through the egg's membrane. It is loaded with a single sperm that will be released into the oocyte. The pictured oocyte has an extruded polar body indicating its maturity. After the procedure, the oocyte will be placed in culture under controlled conditions and examined on the following day for signs of normal fertilization

In natural fertilization sperm compete with each other and when the first sperm enters the egg cell, the egg cell blocks the entry of any other sperm. Concern has been raised that in ICSI this sperm selection process is bypassed and the sperm is selected by the embryologist without any specific testing. However, in mid 2006 the FDA cleared a device that allows the embryologist to select mature sperm for ICSI based on sperm binding to hyaluronan, the main constituent of the layers surrounding the oocyte. The device provides microscopic droplets of hyaluronan hydrogel attached to the culture dish. The embryologist places the prepared sperm on the microdot, selects and captures sperm that bind to the dot. Basic research on the maturation of sperm shows that hyaluronan-binding sperm are more mature and show fewer DNA strand breaks and significantly lower levels of aneuploidy than the sperm population from which they were selected.