Male Infertility

INTRODUCTION

Approximately 15% of all couples have difficulty achieving a pregnancy during their reproductive years. In approximately 50% of these couples, a male factor is involved, either alone or with a coinciding female factor. The spectrum of causes of male infertility is quite variable, as are the appropriate treatments. Fortunately, significant progress has been made in the past decade in both the diagnosis and treatment of these infertile couples. These advances now allow for the successful correction of problems and the ultimate ability to establish a pregnancy for men who just a few years ago had little chance of having a biologic child of their own.

NORMAL MALE REPRODUCTIVE ANATOMY

	Bladder Seminal vesicle Prostate Pubic bone Erectile tissue Urethra Vas deferens (spermatic duct) Epididymis Glans penis Foreskin Testis Rete testis Efferent ductules Seminiferous tubules Anus
Figure 1. The normal male reproductive tract

The testes are paired organs located within the scrotum, which is a multilayered muscular structure that protects the testes and assists in temperature regulation (Fig. 1). The testes have two very important functions, and each of them is essential for normal male fertility:

1. Production of testosterone
2. Production of sperm

The testes are normally 4 to 5 cm long, and they are each encased by a firm, fibrous capsule called the tunica albuginea. Within this capsule, the seminiferous tubules are found (Fig. 2). These tubules are very small structures containing Sertoli cells (support and nurturing cells for the sperm) and the germinal epithelium, the precursor cells that mature into spermatozoa. Along the course of normal seminiferous tubules, one finds sperm present at various stages of development, from the immature spermatogonium to the mature spermatozoon. Surrounding the seminiferous tubules are interstitial cells, which include the Leydig cells (Fig. 3). The primary role of the Leydig cells is to produce testosterone, which is essential for spermatogenesis.

Figure 2. Transverse section of the seminiferous tubules and adjacent interstitial tissue (500x magnification)

The rete testes and efferent ductules are tubes that lead from the testis to the epididymis (Fig. 1). It is through these tubes that sperm pass from the seminiferous tubules to their next destination, the epididymis. The epididymis is a long, narrow duct, approximately 6 meters in length, which is coiled and housed beneath a fibrous sheath. The epididymis sits on the back of the testis, and it is divided into head, body, and tail regions. From the epididymis, sperm proceed into the vas deferens (Fig. 4). The vas deferens is also a long, tubular structure. It arises from the tail of the epididymis and proceeds superiorly in the scrotum with the spermatic cord. The vas travels through the inguinal canal within the spermatic cord, and

Figure 3. The hypothalamic-pituitary-gonadal (HPG) axis.

diverges from the cord behind the abdominal wall, where it then proceeds to the pelvis, terminating in an area behind the prostate. Near the prostate, the vas develops a lateral outpouching, called the seminal vesicle. There are two seminal vesicles, since each develops from the right or left vas. Each seminal vesicle is about 4 cm in length and contributes fructose to the seminal fluid. The seminal vesicle and vas deferens fuse to form the ejaculatory duct, which courses through the prostate to terminate in the urethra (Fig. 5). During ejaculation the seminal fluid, a combination of sperm, prostatic secretions, and seminal vesicle secretions, is expelled out the urethra.

Figure 4. The testicle, epididymis, and vas deterens.

NORMAL MALE REPRODUCTIVE PHYSIOLOGY

The production of sperm capable of achievement of a pregnancy is a very complicated process. The purpose of sperm production is simple - to create a mechanism by which the male's chromosomal material may be combined with that of the female partner to propagate life. This process of active spermatogenesis begins at puberty and lasts, in healthy males, until death.

The production of sperm in the testicle is under hormonal control, which is regulated by the hypothalamus and the pituitary gland in the brain (Fig. 3). This combination is known as the hypothalamic-pituitary-gonadal (HPG) axis. The hypothalamus regulates the hormonal activity of the anterior pituitary gland by secreting gonadotropin-releasing hormone (GnRH), which controls the secretion of follicle~simulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. Under the influence of LH, the Leydig cells within the testes make testosterone, an essential cofactor in spermatogenesis. Under the influence of FSH, Sertoli cells within the testes are stimulated to facilitate the production of sperm by secreting various growth factors. From beginning to end, sperm production takes about 72 days. The first 50 days are spent in the testis and the last 22-24 days in the epididymis. In the epididymis, sperm both mature and gain motility. During sexual activity, motile sperm are ejaculated into the female reproductive tract and thus begin their journey to the fallopian tubes, the site of fertilization.

Figure 5. Sagittal view depicting prostate and ejaculatory duct anatomy

SHOULD I BE EVALUATED?

In the past, couples were instructed to initiate an infertility workup only after at least one year of unsuccessful attempts. Often, the evaluation was limited to the female partner alone. This view has subsequently changed, and couples are now encouraged to proceed with an evaluation when they first suspect a problem with their reproductive function. Issues such as patient anxiety and advanced maternal age are among the factors that have led to this new approach.

For the male patient, the workup should generally begin when the female partner's evaluation is initiated. A male fertility specialist, usually a urologist who has a focus in his practice on male fertility problems as well as some postgraduate training in this area, should perform this workup. The important point, as mentioned earlier, is that a male factor is involved in as many as 50% of infertile couples, and thus a delay in diagnosis may ultimately impair chances for the couple's success.

EVALUATION OF THE MALE PATIENT

HISTORY

The evaluation of the male patient begins with a thorough history. The physician will ask about a number of items, including duration of the problem, sexual habits, prior pregnancies and previous treatment, as well as the general health of the patient. A childhood or developmental history, including questions regarding a history of testicular torsion or postpubertal mumps, is included. The patient's medical and surgical history should be discussed, including items such as a history of diabetes, prostate surgery, or hernia repairs. A discussion of exposure to possible toxic agents such as radiation, heavy metals, and organic solvents should be included.

PHYSICAL EXAMINATION

The physical examination should be thorough and complete. The physician wilt likely pay close attention to the penis and scrotal contents. Testicular size and consistency, as well as the presence or absence of the vas deferens and swelling or tenderness of the epididymides, are noted. For this portion of the examination, the physician may ask you to stand, take a deep breath, and "bear down" (the Valsalva maneuver) as he examines you for the presence of enlarged veins around the testicle (varicoceles). Additionally, a prostate examination is a key aspect of a thorough evaluation.

ROUTINE LABORATORY TESTING

SEMEN ANALYSIS

A central component of laboratory testing is the semen analysis. To perform this, a man is generally asked to obtain a specimen through masturbation. Special containers are also available for home collection, but prompt return of the specimen to the laboratory (within one hour) is mandatory. Collection of the entire specimen is important for accurate diagnosis. A period of 48-72 hours of abstinence should precede the collection. Table 1 lists minimal standards for adequate semen parameters. It is important to note that these values are not the absolute values needed to achieve a pregnancy, but rather statistical limits below which male infertility is more likely to be a problem. Furthermore, significant variation in one or several semen parameters from one specimen to another may be present and is not uncommon. It is for these reasons that at least two semen specimens should be analyzed. Adherence to strict collection techniques and abstinence periods is therefore crucial to minimize variation.

SERUM HORMONE LEVELS

A routine part of the initial evaluation is a determination of specific hormones in the blood, which usually include FSH, LH, testosterone, and prolactin levels. The interrelationship of these four hormones is closely tied to normal sperm production. Abnormalities may be a sign of a primary hormone problem in the hypothalamus, pituitary, or testis.

ADDITIONAL LABORATORY TESTING

Semen Leukocytes: Increased numbers of white blood cells WBC) in the semen have been associated with deficiencies in sperm function and motility. Recently, the development of specialized staining techniques for WBC has allowed their definitive identification within the semen. Semen WBC have been associated with genitouri nary infections and/or inflammation. WBC have also been implicated in the release of harmful substances called reactive oxygen species (ROS). ROS will be discussed at length below. Evidence of elevated levels of WBC in the semen should lead to a semen culture, which is used to identify the presence of infection.

Antisperm Antibody Testing: Antisperm antibodies (ASA) in the semen are associated with lower pregnancy rates. Conditions associated with the presence of seminal ASA include genitourinary infections, testicular trauma, thermal injury, and genital tract obstruction. The most accurate means of detecting ASA is through the use of the Immunobead® test. Microscopic beads are used to detect the presence of sperm-bound antibodies. Greater than 20% of sperm with ASA binding is usually clinically significant and possibly associated with functional sperm deficits.
Under the microscope, the semen of a man with positive ASA may frequently be noted to have excessive clumping and decreased sperm motility.

Reactive Oxygen Species (ROS): ROS are molecules with an extra electron that can be easily passed on to another molecule. When present in excessively high levels, ROS can cause injury to sperm and other genital tract cells. Specifically, this damage can involve the sperm membrane and DNA and may lead to overall impaired sperm function.

Morphology: Morphology assays are descriptive analyses of sperm shape. Several studies have suggested a correlation between sperm morphology and function. Two types of morphology tests used include the "standard" morphology assay and Kruger's strict morphology assay. In the lafter, sperm are actually measured in multiple areas to identify "perfect sperm shape," which should be greater than 4% of the cells examined.

Sperm Penetration Assay (SPA): This is a functional test which evaluates the sperm's ability to penetrate hamster ova. The result of a normal SPA is correlated with a greater incidence of positive in vitro fertilization (IVF) outcomes. Abnormal results may steer a couple towards assisted reproductive techniques using specific sperm separation procedures prior to intrauterine insemination (IUI) or even to intracytoplasmic sperm injection (ICSI) with IVF.

TREATMENT OPTIONS

After a thorough history, physical examination, and diagnostic testing, your physician should be able to recommend treatment options. These have generally been organized into medical and surgical approaches.

MEDICAL THERAPY

1. Human Chorionic Gonadotropin (hCG), Menotropins (hMG) and GnRH Treatments: These agents are generally used for patients with hypogonadotropic hypogonadism, a condition which results in impaired sperm production due to a deficit in essential hormonal levels, specifically [H and FSH. Human chorionic gonadotropin (hCG) behaves much like [H, stimulating the testicular Leydig cells to produce testosterone, and thus overcome the underlying hormonal defect. Human menopausal gonadotropin (hMG) activity is similar to both [H and FSH stimulation, and it has therapeutic effects similar to hCG. GnRH therapy is also used in men with hypogonadotropic hypogonadism, and its role is to increase production of [H and FSH in the brain, thus correcting their low levels in the circulation. Use of these agents outside of the sefting of hypogonadofropic hypogonadism rarely improves semen quality.

2. Clomiphene Citrate: This synthetic compound works primarily at the level of the brain. It binds to estrogen receptors in the hypothalamus and pituitary gland, thus preventing the inhibitory effects (negative feedback) usually exerted by the estrogens that normally bind to those same sites.

Hypothalamic estrogens in the male are formed from aromatization of testosterone. Therefore, in blocking this normal estrogen-negative feedback, clomiphene citrate thus promotes GnRH secretion and, subsequently, also enhanced [H and FSH secretion. As discussed previously, these two hormones result in increased testicular production of testosterone and may improve sperm production as well.

3. Antioxidants: (Vitamin E and Vitamin C): These medications are used primarily to treat molecules called reactive oxygen species (ROS). ROS are normally present in semen, and at normal concentrations they serve a physiologic function. As previously discussed, they possess an extra electron which is very easily passed onto other molecules. When ROS are present at excessively high levels, their cumulative effects can result in significant damage to the sperm and other genital tract cells. These antioxidants help neutralize ROS, thus preventing their harmful effects.

4. Dietary Carnitine Supplements: This is an agent currently under study in the United States. Carnitine is a chemical found in high concentrations within the epididymis. Preliminary studies suggest that supplementation with carnitine may improve sperm motility. Rigorous studies are now under way to confirm or refute these findings and to befter delineate which groups of patients would best benefit from this treatment.

SURGICAL THERAPY

1. Varicocele Ligation: The group of blood vessels which collectively provide the primary venous drainage from the testis are called the pampiniform plexus. Varicoceles are dilated veins in the scrotum surrounding the testis, in other words, dilated pampiniform plexus veins (Figs. 6A & 6B). Two separate groups of veins also effectively drain blood away from the testis.

Figure 6A. Appearance of a visibly evident varicocele.	Figure 6B. Dilated veins of the pampinitarm plexus traveling within the spermatic cord.

Approximately 15% of all men have varicoceles, and for most men they do not seem to impair testicular function. However, about 40% of all men presenting with fertility problems do have varicoceles, and it is generally believed that their presence, either directly or indirectly, impairs sperm production. Although the precise pathophysiologic mechanism of the varicocele effect has not been delineated, many investigators believe that a secondary increase in testicular temperature causes impaired spermatogenesis. Whatever the cause, many studies have demonstrated that 40%-70% of men undergoing varicocele repair will have an improvement in semen quality, and about 40% will subsequently initiate a pregnancy.

Many urologists now prefer an operative approach that employs the use of an operating microscope. The use of this higher magnification better ensures preservation of important spermatic cord structures (e.g., artery and lymphatics) with effective ligation of those veins contributing to the varicocele.

2. Transurethral Resection of the Ejaculatory Duct: As described previously, the ejaculatory duct is a structure formed after the union of the vas deferens and seminal vesicle. It is a tubular structure that proceeds through the prostate on both the right and the left to the respective prostatic portion of the urethra. It is responsible for sperm and seminal vesicle fluid transport into the prostatic urethra, the final destination of sperm prior to ejaculation. A number of factors can cause obstruction of the ejaculatory duct, and thus block the flow of sperm. These include intrinsic problems, such as congenital narrowing or scarring due to infection, and extrinsic problems, such as compression due to a prostatic cyst or tumor.

Obstructed ejaculatory ducts are usually diagnosed by transrectal ultrasound imaging or by special radiographic tests called vasograms. Obstructed ducts are treated by a simple transurethral procedure whereby the obstructed part of the duct is removed, thus leaving normal, unobstructed ductal tissue behind (Fig. 7).

Figure 7. Location of resection in transurethral resection of the ejaculatory ducts.

Figure 8A. Technique for vasovasostomy.

3. Microsurgical Reversal of Vasal or Epididymal Obstruction: Obstruction of the vas deferens is usually the result of a prior elective vasectomy procedure. Over time, this obstruction may lead to significant "backpressure" experienced by the fragile epididymal tubules, thus causing a secondary epididymal obstruction, often referred to as a "blowout." Vasal obstruction, and even secondary epididymal obstruction, can usually be corrected operatively using special microsurgical techniques to bypass the obstruction (Figs. 8-A & 8-B). These microscopic procedures are among the most technically demanding ones performed by urologists, and they are best accomplished by individuals with special training in this area.

Figure 8B. Technique for epididymovasostomy.

4. Sperm Procurement Techniques: Some couples, either as a result of male or female fertility issues, will need to proceed to assisted reproductive techniques such as in vitro fertilization (IVF). In some male patients, sufficient sperm are not available in the ejaculate. This deficiency may be due to problems with sperm production, obstruction of the male reproductive tract, or disorders of ejaculation. Therefore, sperm retrieval techniques must be employed to obtain sperm for use in IVF. The type of procurement technique used depends largely on the nature of the patient's problem. If obstruction or ejaculatory disturbance is the primary issue, then epididymal sperm retrieval is the preferred method. This will typically yield motile, mature sperm. If the problem is one of abnormal sperm production, then usually removal of a small amount of testicular tissue with sperm extraction is performed. Sperm obtained by these techniques are injected directly into the egg, a process known as intracytoplasmic sperm injection (ICSI). Only one live sperm is needed for each egg. Often, sperm obtained via procurement techniques (such as above) can be used fresh in IVF procedures or cryopreserved, and used at a later date.

A BRIEF WORD ABOUT ASSISTED REPRODUCTIVE TECHNIQUES

Assisted reproductive techniques (ART) describe several special methods used to help couples achieve a pregnancy. The first of these is called intrauterine insemination (lUl). IUI involves the collection of the male's ejaculate and subsequent processing or "washing." The elaculate is then inserted into the female's cervix or uterus using a special injection catheter. Among ART this is generally considered to be the least invasive, but its effectiveness is limited for those patients with severe fertility problems.

IVF occurs when the male's sperm is incubated with the female's eggs in the laboratory. The development of the eggs are medically regulated with hormones, and the conditions in the laboratory dish are meticulously controlled to optimize the chances for fertilization. Those eggs which are fertilized (i.e., "embryos") can then be assessed on the basis of their appearance, allowing for the selection and replacement into the female of the best embryos. These embryos have been shown to be the ones with the highest likelihood of resulting in a successful pregnancy. Those embryos not used can be frozen (cryopreserved) for later use.

Figure 9. Intracytoplasmic sperm injection (ICSI).

A modification of the IVF procedure is the ICSI procedure (Fig. 9). ICSI utilizes the same methods as standard IVF except instead of simply incubating the sperm and egg together in a Petri dish, the egg is stabilized under a special microscope using a microsuction instrument while a very fine pipette is used to inject a selected sperm into the egg. This sperm injection technique allows couples to overcome many barriers in sperm count, motility, morphology~ and degree of sperm maturity. ICSI has made it possible for couples, who in the past would have been unable to achieve pregnancies, to bear their own biologic children.

COMMON CONCERNS

What should I expect at the first visit to the doctor?
You should anticipate a thorough history and physical examination. It may be beneficial to have both partners present at this first visit to facilitate data gathering by the physician. This will also allow your partner to have her questions adequately answered in person.

What testing is usually ordered?
Testing will often be initiated at the time of the first visit, and this generally includes measurement of blood hormone levels (FSH, [H, testosterone, and prolactin) to ensure an intact HPG axis. Additionally, you should ask ahead of time if you would be expected to collect a semen sample for semen analysis at that visit. It is usually recommended that men observe two to three days of abstinence prior to undergoing a semen analysis. Most doctors will allow collection of the semen sample at your home, as long as it arrives in the laboratory within one hour.
Other specialized semen testing may be ordered as well, and the patient's clinical history as well as the availability of the specific tests usually determine which tests will be obtained.

I am concerned about my job. How much time should I expect to miss if I have one of the surgical procedure described above?
The majority of the procedures discussed in this booklet can be performed on an outpatient basis. The timing of return to work is variable, depending on the nature of the patient's work duties. Generally, even with the more invasive procedures described above, patients are able to return to work within several days. There may be some activity restrictions for a few weeks, and these should of course be discussed on an individual basis with your physician.

I feel healthy and take care of myself. Could I have done something differently to prevent this from happening?
Most patients with male factor fertility problems are, overall, quite healthy. Although some individuals do develop problems after "preventable events" (exposure to environmental toxins, radiation, trauma, etc.), most causes of male infertility are likely present from birth and thus unavoidable. Unavoidable does not mean untreatable and under the care of a properly trained physician, the chances of a successful pregnancy with subsequent childbirth are optimized.