Chapter 44. Male Infertility

Infertility is defined as the failure to conceive despite 1 year of regular unprotected intercourse. Approximately 15% of couples will experience infertility, and of these, 20% will have a male factor that is solely responsible; male factors will contribute in an additional 30% of cases. In general, male infertility is identified by abnormalities on a semen analysis; however, other issues can contribute to infertility despite normal semen.

The causes of male infertility are widely varied and are best evaluated by a urologist. Some causes of male infertility can be identified and reversed (or improved) with specific surgery or medication while other causes can be identified but not reversed. Occasionally, the underlying cause of infertility or an abnormal semen analysis cannot be identified, in which case it is termed idiopathic. These cases may be amenable to empiric treatment to improve the chances of conception. Before discussing the diagnosis and treatment of male infertility, a review of basic reproductive endocrinology, physiology, and anatomy is in order.

The Hypothalamic–Pituitary–Gonadal Axis

The hypothalamic–pituitary–gonadal (HPG) axis plays a critical role in both the endocrine (testosterone production) and exocrine (sperm maturation) functions of the testes. Several endocrine concepts must be reviewed.

Hormone Classification (Figure 44–1)

Both peptide and steroid hormones are required for communication in the reproductive axis. Peptide hormones are small secretory proteins that bind receptors on the cell surface membrane and induce a series of intracellular events. Hormone signals are transduced by second-messenger pathways whose actions culminate in the phosphorylation of various proteins that alter cell function. The key peptide hormones of the HPG axis are luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

Steroid hormones are derived from cholesterol and, unlike peptide hormones, are not stored in secretory granules. As a result, steroid secretion is limited by the rate of production. Since they are lipophilic, steroid hormones are generally cell membrane permeable. In plasma, steroid hormones are largely bound to serum proteins, with only a small “free” component available to diffuse into the intracellular space and bind receptors. Once bound to an intracellular receptor, steroids are translocated to deoxyribonucleic acid (DNA) recognition sites within the nucleus where they act by regulating the transcription of target genes. The key steroid hormones of the HPG axis are testosterone (T) and estradiol (E2).

Feedback Loops

Normal endocrine and exocrine function of the testes depends on the orchestrated action of numerous hormones. Positive and negative feedback is the principal mechanism through which hormonal regulation occurs. By this mechanism, a hormone can regulate the synthesis and action of itself or of another hormone. Further coordination is provided by hormone action at multiple sites and through multiple responses. In the HPG axis, negative feedback is responsible for minimizing hormonal perturbations and maintaining homeostasis.

Anatomy of the Hypothalamic–Pituitary–Gonadal Axis (Figure 44–2)

Hypothalamus

The hypothalamus receives and integrates neuronal input from the amygdala, thalamus, pons, retina, and cortex. The pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus causes the cyclical secretion of pituitary and gonadal hormones. It is anatomically linked to the pituitary gland by both a portal vascular system and neuronal pathways, thus avoiding the systemic circulation. GnRH is a 10-amino acid peptide secreted from neurons in the preoptic and arcuate nuclei of the hypothalamus. Once secreted into the pituitary portal circulation, GnRH has a half-life of approximately 5–7 minutes, almost entirely removed on the first pass through the pituitary where it stimulates the secretion of FSH and LH.

GnRH secretion is highly responsive to a variety of hormonal and pharmacologic inputs (Table 44–1) and may also be impacted by stress, exercise, and diet. The pulse frequency of GnRH secretion varies from once or twice in 24 hours to every hour and can be abolished by the administration of GnRH agonists.

Anterior Pituitary

The anterior pituitary gland is located within the sella turcica of skull and secretes a series of peptide hormones, including the gonadotropins. GnRH stimulates both production and release of FSH and LH by a calcium flux-dependent mechanism. The sensitivity of the pituitary gonadotrophs for GnRH varies with patient age and hormonal status.

LH and FSH are both glycoproteins composed of alpha and beta subunits, each coded by a separate gene. The alpha subunits of each hormone are identical and are similar to that of all other pituitary hormones; thus, their unique biologic activities are conferred by the beta subunits. Pulsatile secretion of LH varies from 8 to 16 pulses per day with variation in amplitude by one- to threefold. The pulse patterns reflect GnRH release and are regulated by androgens and estrogens through negative feedback. Pulsatile secretion of FSH occurs approximately every 1.5 hours and also demonstrates amplitude variation. Because FSH secretion is smaller in amplitude and has a longer serum half-life, its responsiveness to GnRH is more difficult to measure. In addition to its regulation by serum steroid hormones, FSH appears to have unique and independent responsiveness to the gonadal proteins inhibin and activin.

In the testis, LH stimulates steroidogenesis within Leydig cells by inducing the mitochondrial conversion of cholesterol to pregnenolone and testosterone. FSH binds to Sertoli cells and spermatogonial membranes within the testis and is the major stimulator of seminiferous tubule growth during development and initiates spermatogenesis at puberty. In adults, the major physiologic role of FSH is to maintain quantitatively normal spermatogenesis. Both FSH and LH bind cell surface receptors that activate adenylate cyclase and cause increases in intracellular cyclic adenosine monophosphate (cAMP).

Prolactin is also produced and secreted by the anterior pituitary and can impact both the HPG axis and fertility. Prolactin is a large (23 kDa), globular protein that potentiates milk production and lactation during pregnancy. The role of prolactin in men is poorly understood, but it may increase the concentration of LH receptors on the Leydig cell and may help sustain high intratesticular testosterone levels. It may also potentiate the effects of androgens on the growth and secretions of male accessory sex glands. Normal prolactin levels may be important in the maintenance of libido. Elevated prolactin appears to abolish gonadotropin pulsatility by interfering with episodic GnRH release. Importantly, a markedly elevated prolactin may be evidence of a prolactin-secreting adenoma of the pituitary (prolactinoma) that requires further evaluation.

The Testis

Normal male reproduction requires that the testes have both endocrine (steroid production) and exocrine (sperm maturation and excretion) function. Both of these functions are under the control of the HPG axis. Steroidogenesis occurs in the interstitial compartment, where Leydig cells reside. Spermatogenesis occurs in the seminiferous tubules with the support of Sertoli cells.

Endocrine Testis

Men normally produce approximately 5 g/day. Approximately 2% of testosterone circulates “free” in the serum and is considered the biologically active fraction. The remaining testosterone is bound to sex hormone–binding globulin (SHBG) and, to a slightly lesser extent, albumin within the blood. Several conditions can alter SHBG levels within the blood and thus changing the amount of free or bioavailable testosterone available for tissues. Elevated estrogens and thyroid hormone decrease plasma SHBG and increase the free testosterone fraction, whereas androgens, growth hormone, and obesity increase SHBG levels and decrease the active androgen fraction. Further, as men age, SHBG levels rise. Testosterone is a primary regulator of its own production through negative feedback on the HPG axis.

Testosterone is metabolized into two primary metabolites in target tissues: (1) dihydrotestosterone (DHT) by the enzyme 5-alpha-reductase and (2) estradiol by the enzyme aromatase. DHT is a more potent androgen than testosterone, and in many tissues, the conversion of testosterone to DHT is required for androgen action. While aromatase is present in many tissues, adipocytes play a significant role in the aromatization of testosterone to estradiol. While the mechanisms are still being elucidated, estradiol appears to have a pivotal role in the regulation of the HPG axis.

Exocrine Testis

FSH acts primarily on Sertoli cells within the seminiferous tubules to induce the production of a number of proteins necessary for spermatogenesis, including androgen-binding protein, transferrin, lactate, ceruloplasmin, clusterin, plasminogen activator, prostaglandins, and several growth factors. Through these actions, seminiferous tubule growth is stimulated during development, and sperm production is initiated during puberty and maintained in adulthood.

Inhibin and Activin

Inhibin is a 32-kDa protein derived from Sertoli cells that inhibits FSH release from the anterior pituitary. Inhibin production is stimulated by FSH and acts by negative feedback at the pituitary and hypothalamus. Activin, a peptide hormone with structural homology to transforming growth factor-beta, appears to stimulate FSH secretion through its action on the hypothalamus and pituitary. Activin receptors are found in a host of extragonadal tissues, suggesting that this hormone may have a variety of growth factor or regulatory roles in the body.

Spermatogenesis is a complex process during which primitive, multipotent stem cells divide to either renew themselves or produce daughter cells (mitosis) that further divide (meiosis) to become spermatozoa. These processes occur within the seminiferous tubules of the testis and 80–90% of testis volume is made up of the seminiferous tubules and germ cells at various developmental stages. Thus, it is not surprising that testicular hypotrophy and atrophy are strongly correlated to semen parameters.

Sertoli Cells

Sertoli cells line the seminiferous tubules and are linked by tight junctions. These junctional complexes divide the seminiferous tubule space into basal (basement membrane) and adluminal (lumen) compartments and form the basis for the blood–testis barrier. As a result of this tight junction barrier, spermatogenesis occurs in an immunologically privileged site. Sanctuary from the immune system is critical given that spermatozoa are produced at puberty and therefore contain foreign antigens; immune recognition develops during the first year of life.

Sertoli cells foster spermatogenesis and participate in germ cell phagocytosis. FSH binding to high-affinity FSH receptors on Sertoli cells induces production and secretion of androgen-binding protein. Within the luminal fluid, this protein binds testosterone leading to levels 20–50 times that found in serum. Other regulatory effects of Sertoli cells include the production of inhibin and ligand-receptor complexes, such as c-kit and kit ligand.

Germ Cells

Germ cells are highly ordered within the cross section of the seminiferous tubules. Spermatogonia sit directly on the basement membrane and are followed by primary spermatocytes, secondary spermatocytes, and finally spermatids within the tubular lumen. Thirteen stages of germ cell differentiation have been identified in humans. The tight junctions of Sertoli cells support spermatogonia and early spermatocytes within the basal compartment while all subsequent stages of germ cell development occur within the adluminal compartment. Germ cells are staged by their histologic morphology; there are dark type A (Ad) and pale type A (Ap) and type B spermatogonia and preleptotene, leptotene, zygotene, and pachytene primary spermatocytes, secondary spermatocytes, and Sa, Sb, Sc, Sd1, and Sd2 spermatids (Figure 44–3).

Spermatogenesis is a cyclic process that involves the division of spermatogonial stem cells into elongated spermatids. Several individual cycles of spermatogenesis coexist within the germinal epithelium at a given time. In humans, an entire spermatogenic cycle requires approximately 60–80 days. Cohorts of developmentally similar germ cells are linked by cytoplasmic bridges and mature in unison. This cytoplasmic linkage of cells is organized in a spiral pattern along the seminiferous tubule and results in consistent and stable production of mature sperm.

Genetics of Spermatogenesis

Mitosis is the process by which somatic cells are replicated to form genetically identical daughter cells. Meiosis is the process by which germ cells replicate. As the result of meiosis, daughter cells called gametes are formed which contain one half the genetic material of the parent cell and thus allow for reproduction. This fundamental difference in cell replication generates genetic diversity through natural selection.

A cell's life is divided into cycles that are each associated with different DNA replication activities. Only 5–10% of the cell cycle is spent in the mitotic phase (M), during which time genetic (DNA) and cellular division occur. Mitosis is a precise series of events that requires complete duplication of the genetic material (chromosomes), degeneration of the nuclear envelope, and equal division of chromosomes and cytoplasm into two daughter cells (Table 44–2). The difference between mitotic and meiotic replication is that in mitosis, a single DNA duplication is followed by one cell division; however, in meiosis, two-cell divisions take place to create four daughter cells (Figure 44–4). As a consequence, following meiosis, daughter cells (gametes) contain only half of the chromosome content of the parent cell and are said to be haploid (n) as opposed to diploid (2n). Other major differences between mitosis and meiosis are outlined in Table 44–3.

Stages of Spermatogenesis

From puberty onward, the process of spermatogenesis requires rapid and organized cell division, the likes of which are not seen in other cell lines of the human body. As a result, these highly specialized cells are produced in large quantities; up to 300 sperm per gram of testis tissue per second. Type B spermatogonia undergo mitosis to produce diploid primary spermatocytes (2n), which then duplicate their DNA during interphase. After the first meiotic division, each daughter cell contains a single partner of the homologous chromosome pair and are termed secondary spermatocytes (2n). During the second meiotic division, the chromatids separate at the centromere, yielding haploid spermatids (n).

Spermiogenesis

Spermiogenesis is the process by which spermatids mature to become elongated spermatozoa within the basilar compartment of the seminiferous tubules. This process requires several weeks, and requires the following: (1) formation of the acrosome from the Golgi body, (2) formation of the flagellum from the centriole, (3) reorganization of the mitochondria around the midpiece, (4) extensive compaction of nuclear material, and (5) elimination of residual cytoplasm.

Many cellular elements contribute to the cellular morphologic changes during spermiogenesis, including chromosome structure, associated chromosomal proteins, the perinuclear cytoskeletal theca layer, the microtubules in the nucleus, subacrosomal actin, and Sertoli cell interactions. With completion of spermatid elongation, the Sertoli cell cytoplasm retracts around the developing sperm, stripping it of all unnecessary cytoplasm and extruding it into the tubule lumen. The mature sperm has remarkably little cytoplasm.

Sperm Maturation

Testicular spermatozoa have limited or no motility and are therefore incapable of naturally fertilizing an egg (which has significant clinical implications). They become functional only after traversing the epididymis and where further maturation occurs. Anatomically, the epididymis is divided into three regions: caput or head, corpus or body, and cauda or tail. While the process of epididymal sperm maturation is still being elucidated, it is clear that several changes occur in sperm as they transit through the epididymis. These changes include alterations in cell membrane polarity, membrane protein composition, immunoreactivity, phospholipid and fatty acid content, and adenylate cyclase activity. A sperm's transit time through the epididymis is approximately 10–15 days.

During natural conception, fertilization generally occurs within the ampullary portion of the fallopian tubes. Ovulation typically occurs during the middle of the female menstrual cycle and can be predicted by timing, change in body temperature, chemical detection of the luteinizing hormone surge, or by changes in cervical mucus. This mucus becomes more abundant and watery, thereby facilitating the entry of sperm into the uterus and protecting it from the acidic vaginal environment. Once within the female reproductive tract, sperm undergo physiologic changes referred to as capacitation.

Upon making contact with the egg, sperm undergo hyperactivation, characterized by profound changes in motility (large, lashing motions of the sperm tail). Lytic enzymes are released from the acrosome to allow penetration of the outer surface of the egg. Upon completion of the acrosome reaction, contact between sperm and egg is mediated by specific ligands and receptors on the surface of each gamete.

Once a single sperm enters the zona pellucida of the ovum, it becomes impenetrable to additional sperm. Upon fertilization, the egg resumes meiosis and forms a metaphase II spindle. The sperm centriole, contained within the midpiece, is crucial for early spindle formation and ongoing embryogenesis.

The purpose of the male infertility evaluation is to (1) identify and correct the reversible causes of male infertility with the goal of allowing a couple to conceive through intercourse, or with the least amount of technology; (2) identify irreversible conditions that may be amenable to treatment with assisted reproductive technology (ART) using the male partner's sperm; (3) identify irreversible conditions in which the man's sperm are not obtainable, in which case the couple may consider donated sperm or adoption; (4) identify medical diseases that may be associated with infertility and require treatment; and (5) identify specific genetic causes of infertility that may be transmitted to and impact offspring. Given that a male factor can be the cause of infertility in 30–40% of couples and is a contributing factor in 50% of cases, it is important to evaluate both partners in parallel. A complete urologic evaluation is important because male infertility may be the presenting symptom of otherwise occult but significant systemic disease. A complete evaluation must be comprehensive.

History

A man's evaluation begins with a thorough reproductive, medical, and surgical history (Table 44–4). Important components of this history include (1) duration of infertility, coital timing and frequency, and sexual health; (2) prior paternity or fertility treatments; (3) childhood illnesses and development; (4) medical illnesses, prior infections, and medications; (5) prior surgeries or traumas; and (6) exposure to potential gonadal toxins, such as heat, radiation, chemical solvents, or pesticides.

A sexual history is important as many couples do not know how to precisely time intercourse to achieve a pregnancy. Following intercourse, sperm reside within the cervical mucus and crypts for 1–2 days and can survive longer; thus, an appropriate frequency of intercourse is every 2 days. Water-based lubricants such as K-Y Jelly, most skin lotions, and saliva can reduce sperm motility in vitro and should be avoided. If needed, acceptable lubricants include vegetable, safflower, and peanut oils as well as egg whites.

A general medical and surgical history is also important. Fever or acute infection can decrease testis function and semen quality. Given that spermatogenesis generally requires at least 60 days to complete, the impact of such insults may not be observable in the semen until 2 months after the event. Surgical procedures on the bladder, retroperitoneum, or pelvis can lead to infertility by causing ejaculatory dysfunction due to damage to the bladder neck, sympathetic nerves, or pelvic nerve plexus, respectively. Hernia surgery can result in obstruction of the vas deferens in 1% of cases; this incidence may be rising because of the recent increased use of highly inflammatory mesh patches.

Childhood diseases can have a significant impact on fertility. Severe unilateral orchitis occurs in approximately one-third of postpubertal mumps infections and bilateral orchitis in 10%. Mumps orchitis likely causes pressure necrosis of testis tissue due to severe edema with the later development of testis atrophy. Cryptorchidism is associated with decreased sperm production. This is true for both unilateral and bilateral cases. Longitudinal studies of affected boys have shown that abnormally low sperm counts can be found in 30% of men with unilateral cryptorchidism and 50% of men with bilateral undescended testes. While difficult to study from an epidemiologic standpoint, cryptorchidism appears to result in a higher risk of infertility. Similar to testicular cancer risk, early orchidopexy may reduce the risk of spermatogenic failure.

Exposure and medication histories are very relevant to fertility. Decreased sperm counts have been demonstrated in workers exposed to specific pesticides, which may alter normal testosterone/estrogen hormonal balance. Exposure to ionizing radiation can cause temporary reductions in sperm production with as little as 10 cGy and more permanent or severe reductions with higher doses. Several medications (Table 44–5) and ingestants such as tobacco, cocaine, and marijuana have all been implicated as gonadotoxins. The effects of these agents may be reversible on withdrawal. Anabolic steroids, often taken to increase muscle mass and development, act as contraceptives by inhibiting the pituitary–gonadal axis. Routine exposure to moist heat by use of hot tubs or saunas should be discouraged, as these activities can elevate intratesticular temperature and impair sperm production. Other characteristics associated with impaired fertility include obesity, electromagnetic radiation exposure (eg, significant exposure to high-voltage power lines, cell phones in the “on” position), occupational status (eg, dry cleaners, painters, farm workers), and job-related or other psychological stress.

The family and developmental histories may also provide clues to the infertility etiology. A family history of cystic fibrosis (CF), a condition associated with congenital absence of the vas deferens (CAVD), or intersex conditions is important. The existence of siblings with fertility problems may suggest that a Y chromosome microdeletion or a cytogenetic (karyotype) abnormality is present in the family. A history of delayed onset of puberty could suggest Kallmann or Klinefelter syndrome. A history of recurrent respiratory tract infections may suggest a ciliary defect characteristic of the immotile cilia syndromes. It is important to remember that reproductive technologies enable most men afflicted with such conditions to become fathers and therefore allow for the perpetuation of genetic abnormalities that may not be normally sustained.

Physical Examination

A complete examination of the infertile male is important to identify general health issues associated with infertility. For example, the patient should be adequately virilized; signs of decreased body hair or gynecomastia may suggest androgen deficiency.

The scrotal contents should be carefully palpated with the patient standing. As it is often psychologically uncomfortable for young men to be examined, one helpful hint is to make the examination as efficient and matter of fact as possible. Two features should be noted about the testis: size and consistency. Size is assessed by measuring the long axis and width; as an alternative, an orchidometer can be placed next to the testis for volume determination (Figure 44–5). Standard values of testis size have been reported for normal men and include a mean testis length of 4.6 cm (range, 3.6–5.5 cm), a mean width of 2.6 cm (range, 2.1–3.2 cm), and a mean volume of 18.6 mL (± 4.6 mL) (Figure 44–6). Consistency is more difficult to assess but can be described as firm (normal) or soft (abnormal). Testes that are smaller than normal volume are termed hypotrophic, whereas those that are softer than normal are termed atrophic. Both conditions suggest impaired spermatogenesis.

The peritesticular area should also be examined. Irregularities of the epididymis, located posterior-lateral to the testis, include induration, tenderness, or cysts. The presence or absence of the scrotal vas deferens is critical to observe, as 2% of infertile men may present with CAVD.

Engorgement of the pampiniform plexus of veins in the scrotum is indicative of a varicocele. Asymmetry of the spermatic cords is the usual initial observation, followed by the feeling of a “bag of worms” when retrograde blood flow through the pampiniform veins occurs with a Valsalva maneuver. Varicoceles are usually found on the left side (90%) and are commonly associated with atrophy of the left testis. A discrepancy in testis size between the right and left sides should alert the clinician to this possibility.

Prostate or penile abnormalities should also be noted. Penile abnormalities such as hypospadias, abnormal curvature, or phimosis could result in inadequate delivery of semen to the upper vaginal vault during intercourse. Prostatic infection may be detected by the finding of a boggy, tender prostate on rectal examination. Prostate cancer, often suspected with unusual firmness or a nodule within the prostate, can occasionally be diagnosed in infertile men. Enlarged seminal vesicles, indicative of ejaculatory duct obstruction (EDO), may also be palpable on rectal examination.

Laboratory Testing

Laboratory testing is an important part of the male infertility evaluation.

Semen Analysis

A carefully performed semen analysis is the primary source of information on sperm production and reproductive tract patency. However, it is not a measure of fertility. An abnormal semen analysis simply suggests the likelihood of decreased fertility. Studies have established that there are certain limits of adequacy below which it may be difficult to initiate a pregnancy. These semen analysis values were identified by the World Health Organization (2009) and are considered the minimum criteria for “normal” semen quality (Table 44–6). It is statistically more difficult to achieve a pregnancy if a semen parameter falls below any of those listed. Of these semen variables, the count and motility appear to correlate best with fertility.

Semen Collection

Semen quality can vary widely in a normal individual from day to day, and semen analysis results are dependent on collection technique. For example, the period of sexual abstinence before sample collection is a large source of variability. With each day of abstinence (up to 1 week), semen volume can rise by up to 0.4 mL, and sperm concentration can increase by 10–15 million/mL. Sperm motility tends to fall when the abstinence period is longer than 5 days. For this reason, it is recommended that semen be collected after 48–72 hours of sexual abstinence.

To establish a baseline of semen quality, at least two semen samples are needed. Semen should be collected by self-stimulation; by coitus interruptus (less ideal); or with a special, nonspermicidal condom into a clean glass or plastic container. Because sperm motility decreases after ejaculation, the specimen should be analyzed within 1 hour of procurement. During transit, the specimen should be kept at body temperature.

Physical Characteristics and Measured Variables

Fresh semen is a coagulum that liquefies 15–30 minutes after ejaculation. Ejaculate volume should be at least 1.5 mL, as smaller volumes may not sufficiently buffer against vaginal acidity. Low ejaculate volume may indicate retrograde ejaculation, EDO, incomplete collection, or androgen deficiency. Sperm concentration should be >20 million sperm/mL. Sperm motility is assessed in two ways: the fraction of sperm that are moving and the quality of sperm movement (how fast, how straight they swim).

Sperm cytology or morphology is another measure of semen quality. By assessing the exact dimensions and shape characteristics of the sperm head, midpiece, and tail, sperm can be classified as “normal” or not. In the strictest classification system (Kruger morphology), only 14% of sperm in the ejaculate are normal looking. In fact, this number correlates with the success of egg fertilization in vitro and thus is ascribed real clinical significance. In addition, sperm morphology is a sensitive indicator of overall testicular health, because these characteristics are determined during spermatogenesis. The role of sperm morphology in the male infertility evaluation is to complement other information and to better estimate the chances of fertility.

Computer-Assisted Semen Analysis

In an effort to remove the subjective variables inherent in the manually performed semen analysis, computer-aided semen analyses (CASAs) couple video technology with digitalization and microchip processing to categorize sperm features by algorithms. Although the technology is promising, when manual semen analyses are compared with CASA on identical specimens, CASA can overestimate sperm counts by 30% with high levels of contaminating cells such as immature sperm or leukocytes. In addition, at high sperm concentrations, motility can be underestimated with CASA. CASA has accepted value in the research setting and in some clinical laboratories.

Semen Leukocyte Analysis

White blood cells (leukocytes) are present in all ejaculates and play important roles in immune surveillance and clearance of abnormal sperm. Leukocytospermia or pyospermia, an increase in leukocytes in the ejaculate, is defined as >1 × 106 leukocytes/mL semen but is not a significant cause of male subfertility and its treatment is debated. The prevalence of leukocytospermia ranges from 2.8% to 23% of infertile men. In general, neutrophils predominate among inflammatory cells (Table 44–7). This condition is detected by a variety of diagnostic assays, including differential stains (eg, Papanicolaou), peroxidase stain that detects the peroxidase enzyme in neutrophils, and immunocytology.

Antisperm antibodies (ASAs) can be found in three locations: serum, seminal plasma, and sperm bound. Among these, sperm-bound antibodies are the most relevant. The antibody classes that appear to be clinically relevant include immunoglobulin G (IgG) and IgA. IgG antibody is derived from local production and from transudation from the bloodstream (1%). IgA is thought to be purely locally derived.

Adjunctive Semen Tests: Seminal Fructose and Postejaculate Urinalysis

Fructose is a carbohydrate that is secreted in high concentration from the seminal vesicles and is normally present in the ejaculate. When absent, seminal vesicle agenesis or obstruction may exist. Seminal fructose testing is indicated in men with low ejaculate volumes and no sperm. A postejaculate urinalysis inspects the first voided urine after ejaculation for the presence of sperm. If sperm is identified in the urine, a diagnosis of retrograde ejaculation is made. This test is indicated when the ejaculate volume is below normal (Table 44–8).

Antisperm Antibody Test

The testis is an immunologically privileged site due to the blood–testis barrier formed by the sertoli cell tight junctions. Autoimmune infertility may result when the blood–testis barrier is broken and the body is exposed to sperm antigens. Trauma to the testis and vasectomy are two common ways in which this occurs, giving rise to ASAs. ASA may be associated with impaired sperm transport through the reproductive tract or impairment in egg fertilization. An assay for ASA should be considered when (1) semen analyses show persistent sperm agglutination or clumping; (2) low sperm motility with history of testis injury or surgery; (3) idiopathic leukocytospermia; or (4) unexplained infertility.

Hypoosmotic Swelling Test

Motility is the most commonly used measure of a sperm's viability. Studies have suggested, however, that some nonmotile sperm may still be viable. Indeed, there are clinical conditions, such as immotile-cilia syndrome or testicular sperm, in which there may be immotile but otherwise healthy, viable sperm. Given that these sperm may be used in conjunction with intracytoplasmic sperm injection (ICSI) to form healthy embryos, it is clinically important that they are identifiable. Cell viability can be evaluated noninvasively by using the physiologic principle of hypoosmotic swelling. Viable cells with functional membranes swell when placed in a hypoosmotic environment. This response is easily observed in sperm as tail coiling generally accompanies head swelling. This sperm test is indicated in cases of complete absence of sperm motility.

Sperm Penetration Assay

It is possible to measure the ability of human sperm to penetrate a specially prepared hamster egg in the laboratory setting. The hamster egg allows interspecies fertilization but no further development. This form of bioassay can give important information about the ability of sperm to undergo the capacitation process as well as penetrate and fertilize the egg. Infertile sperm would be expected to penetrate and fertilize a lower fraction of eggs than normal sperm. The indications for the diagnostic sperm penetration assay (SPA) are limited to situations in which functional information about sperm is needed, that is, to further evaluate couples with unexplained infertility and to help couples decide whether intrauterine insemination (IUI) (good SPA result) or in vitro fertilization (IVF) and micromanipulation (poor SPA result) is the appropriate next treatment.

Sperm DNA Fragmentation Assay

There is growing evidence that the integrity of sperm DNA is important for male fertility. Double- and single-stranded breaks in sperm DNA can be measured by several methods, including the COMET and TUNEL assays with or without the use of flow cytometry. These tests assess the degree of DNA fragmentation that occurs after chemically stressing the sperm DNA–chromatin complex, and can indirectly reflect the quality of sperm DNA–chromatin complex and can indirectly reflect the quality of sperm DNA integrity. Abnormally fragmented sperm DNA rarely occurs in fertile men, but can be found in a larger percentage of infertile men with otherwise normal semen analyses. This test can detect infertility that is missed on a conventional semen analysis. Often reversible, causes of DNA fragmentation include tobacco use, medical disease, hyperthermia, air pollution, infections, and varicocele.

Hormone Assessment

Evaluation of the pituitary–gonadal axis provides valuable information on the state of sperm production. Furthermore, abnormal function of the HPG axis can be an underlying cause of poor sperm production and infertility (hyperprolactinemia, gonadotropin deficiency, congenital adrenal hyperplasia). In general, FSH and testosterone should be measured in infertile men with sperm concentrations of <10 × 106 sperm/mL. Testosterone is a measure of overall endocrine balance and likely plays a critical role in spermatogenesis. In most cases, FSH reflects the state of sperm production: when spermatogenesis is impaired at the testicular level, FSH should be elevated. This combination of tests will detect most (99%) endocrine abnormalities. Serum LH and prolactin levels may be obtained if testosterone and FSH are abnormal. In the setting of low testosterone, free testosterone should be assessed. Given the role of estradiol in regulating the HPG axis, it too should be assessed if there is evidence of poor virilization or obesity. Thyroid hormone, liver function, and other organ-specific tests should be obtained if there is clinical evidence of active disease, as uncontrolled systemic illness can affect sperm production. The common patterns of hormonal disorders observed in infertility are given in Table 44–9.

With relatively normal spermatogenesis, low levels of plasma LH and FSH have no clinical meaning; likewise, an isolated low LH with normal testosterone is not significant. Additional indications for hormone evaluation of infertile men include impaired sexual function (low libido, erectile dysfunction) and findings suggestive of a specific endocrinopathy (eg, thyroid). On initial testing, approximately 10% of infertile men will have an abnormal hormone level, with clinically significant endocrinopathies occurring in 2% of men.

Genetic Tests

Chromosomal Studies

Subtle genetic abnormalities can present as male infertility. It is estimated that between 2% and 15% of infertile men with azoospermia (no sperm count) or severe oligospermia (low sperm counts) will harbor a chromosomal abnormality on either the sex chromosomes or autosomes. A blood test for cytogenetic analysis (karyotype) can determine if such a genetic anomaly is present. Patients at risk for abnormal cytogenetic findings include men with small, atrophic testes; elevated FSH values; and azoospermia. Klinefelter syndrome (XXY) is the most frequently detected sex chromosomal abnormality among infertile men (Figure 44–7).

Cystic Fibrosis Mutation Testing

A blood test is indicated for infertile men who present with CF or the much more subtle condition, CAVD. Similar genetic mutations are found in both patients, although the latter group is generally considered to have an atypical form of CF, in which the scrotal vas deferens is nonpalpable. Approximately 80% of men without palpable vasa will harbor a CF gene mutation. Recent data also indicate that azoospermic men with idiopathic obstruction and men with a clinical triad of chronic sinusitis, bronchiectasis, and obstructive azoospermia (OA) (Young syndrome) may be at higher risk for CF gene mutations.

Y Chromosome Microdeletion Analysis

As many as 7% of men with oligospermia and 15% of men with azoospermia have small, underlying deletions in one or more gene regions on the long arm of the Y chromosome (Yq). Several regions of the Y chromosome have been implicated in spermatogenic failure, identified as AZFa, b, and c (Figure 44–8). Deletion of the DAZ (deleted in azoospermia) gene in the AZFc region is the most commonly observed microdeletion in infertile men. Fertility is possible in most men with these deletions with IVF and micromanipulation of sperm. A polymerase chain reaction–based blood test can examine the Y chromosome from peripheral leukocytes for these gene deletions and is recommended for men with low or no sperm counts and small, atrophic testes.

Adjunctive Tests

Urinalysis

A urinalysis is a simple test that can be performed during the initial office visit. It may indicate the presence of infection, hematuria, glucosuria, or renal disease, and as such may suggest anatomic or medical problems within the urinary tract.

Semen Culture

Seminal fluid that passes through the urethra is routinely contaminated with bacteria. This can make the interpretation of semen culture difficult. Semen cultures should only be obtained in selected situations and approximately 13% of infertile men will have positive semen cultures; the relationship between bacterial cultures and infertility is controversial. Semen cultures should be considered when there is evidence of infection, including (1) a history of genital tract infection, (2) abnormal expressed prostatic secretion, (3) the presence of >1000 pathogenic bacteria per milliliter of semen, and (4) the presence of >1 × 106 leukocytes/mL of semen (pyospermia).

The agents most commonly responsible for male genital tract infections are listed in Table 44–10. Gonorrhea is the most common infection. About 10–25% of chlamydial infections may be asymptomatic. Trichomonas vaginalis is a protozoan parasite responsible for 1–5% of nongonococcal infections; it is usually symptomatic. Ureaplasma urealyticum is a common inhabitant of the urethra in sexually active men (30–50% of normal men) and is responsible for one-fourth of all cases of nongonococcal infections. Escherichia coli infections are relatively uncommon in young men and are usually symptomatic. Mycoplasmas are aerobic bacteria that are known to colonize the male reproductive tract. Rarer but possible causes of infection include anaerobic bacteria and tuberculosis.

Radiologic Testing

Scrotal Ultrasound

High-frequency ultrasound of the scrotum is commonly performed for the evaluation of testicular, paratesticular, and scrotal lesions that cannot be completely evaluated on physical examination. Scrotal ultrasound is indicated in men who have a hydrocele, whereby the testis is nonpalpable. Any abnormality of the peritesticular region should also undergo a scrotal ultrasound to determine its characteristics or origin.

Scrotal color Doppler ultrasonography has been used to investigate varicoceles (Figure 44–9). By combining measurements of blood-flow patterns (the presence of retrograde venous flow) and vein size, both physiologic and anatomic information can be obtained to confirm the diagnosis. Although diagnostic criteria that define a varicocele vary widely, a pampiniform venous diameter of >3 mm is considered abnormal. Retrograde blood flow through the veins with a Valsalva maneuver is a key radiologic feature of a varicocele.

Venography

Historically, venography has been described as the most sensitive way to diagnose varicoceles. Although found by palpation in approximately 30–40% of subfertile men, varicoceles can be detected by venography in 70% of patients. This test is invasive, expensive, and technician dependent; at present, its main indications are to guide simultaneous percutaneous varicocele embolization and it is virtually never utilized as a stand-alone diagnostic test. The test is performed through percutaneous canalization of the internal jugular vein or common femoral vein. Venographically, a varicocele is defined by a Valsalva-induced retrograde flow, of contrast material from the renal vein into the scrotal pampiniform plexus.

Transrectal Ultrasound

High-frequency (5–7 mHz) transrectal ultrasound (TRUS) can provide good anatomic detail of the prostate, seminal vesicles, and ejaculatory ducts. Dilation of the seminal vesicles (>1.5 cm in width) or ejaculatory ducts (>2.3 mm) in association with a cyst, calcification, or stones along the duct is highly suggestive of obstruction (Figure 44–10). Among infertile men, TRUS is indicated in cases of low ejaculate volume (<1.5 mL) not explained by retrograde ejaculation or abnormal hormones.

Computed Tomography Scan or Magnetic Resonance Imaging of the Pelvis

The imaging techniques of computed tomography (CT) and magnetic resonance imaging (MRI) can further define reproductive tract anatomy. However, since the advent of TRUS, these studies have relatively few indications. They include evaluation of a patient with a solitary right varicocele, which may be associated with retroperitoneal pathology, and evaluation of the nonpalpable testis.

Testis Biopsy and Vasography

The diagnostic testis biopsy is an important adjunct to the infertility evaluation as it provides direct information regarding the state of spermatogenesis. Most commonly, the technique involves a small, open incision in the scrotal wall and testis tunica albuginea under local or general anesthesia. A small sample of testis tissue is removed, fixed in formalin or Bouin's solution, and examined histologically. Abnormalities of seminiferous tubule architecture and cellular composition are then categorized into several patterns. This procedure is generally reserved for azoospermic men, in whom it may be difficult to distinguish between a failure of sperm production (nonobstructive azoospermia [NOA]) and obstruction within the reproductive tract ducts (OA). A testis biopsy allows delineation between these conditions and can guide further treatment options in azoospermic men (Figure 44–11).

In azoospermic men with normal ejaculate volume and evidence of normal spermatogenesis by testis biopsy, formal investigation of the reproductive tract to identify the site of obstruction is warranted. A vasogram involves the injection of contrast media into the vas deferens toward the bladder from the scrotum. In plain film radiographs or fluoroscopy, contrast material can delineate the proximal vas deferens, seminal vesicle, and ejaculatory duct anatomy and determine whether obstruction is present. Similar information, albeit without anatomic detail, can be obtained with chromotubation, whereby dye (indigo carmine, methylene blue) is injected while the ejaculatory ducts are visualized by cystourethroscopy. Sampling of vasal fluid during the same procedure can also determine whether sperm exist within the testicular end of the vas deferens. Vasal sperm presence implies that there is no obstruction in the testis or epididymis. With this information, the site of obstruction can be accurately determined and potentially surgically corrected.

Biopsy is generally not indicated for oligospermia unless it is severe or alternates with azoospermia (cryptozoospermia). While a unilateral testis biopsy is usually sufficient, the finding of asymmetric testes warrants bilateral biopsies. This situation may reflect a unilateral unobstructed failing testis paired with a normal obstructed testis. Historically, testis biopsy has been proposed to identify patients at high risk for intratubular germ cell neoplasia. This premalignant condition exists in 5% of men with a contralateral germ cell tumor of the testis and is more prevalent in infertile men than in fertile men. Importantly, while there is strong evidence that infertile men have higher risk for testicular cancer, their absolute risk for cancer remains low and most cancers will present with a painless testicular mass. In general, the purpose of biopsy is for identifying the presence or absence of sperm, and not for cancer diagnosis.

Testis biopsy may also be performed to obtain sperm for use with ART. Testicular sperm that are harvested by biopsy are now routinely used to help men with severe male-factor infertility to achieve fatherhood. Sperm retrieval techniques are discussed in subsequent sections.

Multisite Fine-Needle Aspiration of Testes (Figure 44–12)

Testicular sperm is used with IVF and ICSI to achieve pregnancies; however, there is a failure to obtain sperm in 25–50% of men with spermatogenic failure. When testis biopsies fail to retrieve sperm, IVF cycles are canceled at great emotional and financial cost. To minimize the chance of failed sperm retrieval, percutaneous fine-needle aspiration (FNA) of the testis has been described. This technique can accurately diagnose and classify the severity of disease in men with azoospermia or severe oligospermia. Cytological analysis with FNA has a high correlation with histological specimens from open testicular biopsies. In some men, FNA may be more sensitive at detecting a heterogenous pattern of intratesticular spermatogenesis.

Similar to a testis biopsy, FNA is performed under local anesthesia. Percutaneously aspirated (with a 23G needle) seminiferous tubules from various locations in the testis are smeared on a slide, fixed, stained, and read by an experienced andrologist or cytopathologist for the presence of sperm. The information gained from this technique can fully inform patients of their chances of subsequent sperm retrieval for IVF and ICSI.

The causes underlying male infertility are numerous and best categorized by effects at one or more of the following levels: pretesticular, testicular, and posttesticular.

Pretesticular

Conditions that cause infertility that act at the pretesticular level tend to be hormonal in nature (Table 44–11).

Hypothalamic Disease

Gonadotropin Deficiency (Kallmann Syndrome)

Kallmann syndrome (1:30,000) is characterized by central hypogonadism, delayed in puberty, and infertility. Other clinical features include anosmia, small testes and occasionally renal agenesis, bimanual synkinesia, cleft lip, and dental agenesis. When anosmia is not present, the condition is termed idiopathic hypogonadotrophic hypogonadism (IHH). The clinical diagnosis of Kallmann syndrome is confirmed by hormonal assessment revealing low testosterone, low LH, low FSH, and normal prolactin levels. Infertility is treatable with gonadotropin (LH and FSH) replacement over 12–18 months, which induces sperm in the ejaculate in 80% of men. The condition is inherited as a familial disorder in one-third of cases and both X-linked and autosomal inheritance patterns have been described. In the X-linked recessive form, deletions of the KAL1 gene prevent migration of GnRH neurons to the preoptic area of the hypothalamus during embryologic development.

Isolated Gonadotropin Deficiencies

These deficiencies are rare. As the result of a partial LH deficit, there is enough LH to stimulate intratesticular testosterone production and spermatogenesis but insufficient testosterone to promote virilization. The results are a eunuchoid body habitus, variable virilization, and gynecomastia. These men usually have normal size testes, but sperm concentration is low. Plasma FSH levels are normal, but serum LH and testosterone levels are low normal.

With insufficient FSH production by the pituitary, patients are normally virilized, testicular size is normal, and LH and testosterone levels are normal. FSH levels are uniformly low and do not respond to stimulation with GnRH. Sperm counts range from azoospermia to severely low numbers (oligospermia).

Congenital Hypogonadotrophic Syndromes

Several syndromes may be associated with secondary hypogonadism. Prader–Willi syndrome (1:20,000) is characterized by obesity, mental retardation, small extremities, and hypogonadism and is caused by a deficiency of hypothalamic GnRH. The cause of this condition appears to be a single gene deletion on chromosome 15. Similar to Kallmann syndrome, spermatogenesis can be induced by treatment with FSH and LH. Bardet–Biedl syndrome is an autosomal recessive form of hypogonadotrophic hypogonadism that also results from GnRH deficiency. It is characterized by mental retardation, retinitis pigmentosa, polydactyly, and hypogonadism. The presentation is similar to Kallmann syndrome but includes obesity and may also be treated with gonadotropin administration. Cerebellar ataxia can be associated with hypogonadotrophic hypogonadism. Cerebellar involvement includes abnormalities of speech and gait and these patients can have a eunuchoid appearance with atrophic testes. Hypothalamic–pituitary dysfunction due to pathologic changes in cerebral white matter is thought to underlie infertility.

Pituitary Disease

Pituitary Insufficiency

Pituitary insufficiency may result from tumors, infarcts, surgery, radiation, or infiltrative and granulomatous processes. In sickle cell anemia, pituitary and testicular microinfarcts result from sickling of red blood cells potentially leading to both hypogonadism and spermatogenic failure. Men with sickle cell anemia have decreased testosterone and variable LH and FSH levels. Beta-thalassemia occurs primarily in patients of Mediterranean or African origin and is caused by mutations in the beta-globulin that leads to abnormal hemoglobin composition and subsequent red cell lysis. Infertility results from the deposition of hemosiderin in the pituitary gland and testes. Similarly, hemochromatosis results in iron deposition within the liver, testis, and pituitary and is associated with testicular dysfunction in 80% of cases.

Hyperprolactinemia

Elevations of circulating prolactin can cause hypogonadotropic hypogonadism. If hyperprolactinemia is identified, secondary causes such as stress during the blood draw, systemic illness, or medications should be ruled out. With these causes excluded, the most common and important cause of hyperprolactinemia is a prolactin-secreting pituitary adenoma, or prolactinoma. MRI of the sella turcica has classically been used to distinguish between microadenoma (<10 mm) and macroadenoma (>10 mm) forms of tumor.

Stratification of disease based on radiologic diagnosis alone is misleading, as surgery for hyperprolactinemia almost always reveals a pituitary tumor. Elevated prolactin typically results in suppression of gonadotropin production, with subsequent declines in testosterone levels and spermatogenesis. Symptoms of hyperprolactinemia may include loss of libido, erectile dysfunction, gynecomastia, and galactorrhea. Signs and symptoms of other pituitary hormone derangements (adrenocorticotropic hormone, thyroid-stimulating hormone) should also be investigated.

Exogenous or Endogenous Hormones

Estrogens

An excess of sex steroids, either estrogens or androgens, may cause infertility due to an imbalance of the testosterone estrogen ratio, which is normally 10:1. Liver cirrhosis increases endogenous estrogens due to augmented aromatase activity within the diseased liver. Likewise, obesity may be associated with testosterone and estrogen imbalance owing to increased peripheral aromatase activity in adipocytes. Less commonly, adrenocortical tumors, Sertoli cell tumors, and interstitial testis tumors may produce estrogens. Excess estrogens cause spermatogenic failure by decreasing pituitary gonadotropin secretion, thus inducing secondary testis failure.

Androgens

An excess of androgens can suppress pituitary gonadotropin secretion and lead to secondary testis failure. The use of exogenous androgenic steroids (anabolic steroids) by as many as 15% of high school athletes, 30% of college athletes, and 70% of professional athletes may result in temporary sterility due to suppression of the normal HPG axis. Treatment includes immediate discontinuation of steroids and reevaluation of semen quality every 3–6 months until spermatogenesis returns. The most common reason for excess endogenous androgens is congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. The resultant absence of cortisol synthesis and excessive adrenocorticotropic hormone production leads to elevated androgenic steroids by the adrenal cortex. High androgen levels in prepubertal boys result in precocious puberty, with premature development of secondary sex characteristics and abnormal enlargement of the phallus. The testes are characteristically small because of central gonadotropin inhibition by androgens. In young girls, virilization occurs with clitoral enlargement. In cases of classic congenital adrenal hyperplasia that presents in childhood, normal sperm counts and fertility have been reported, even without glucocorticoid treatment. This disorder is one of the few intersex conditions associated with potentially normal fertility. Other sources of endogenous androgens include hormonally active adrenocortical tumors or Leydig cell tumors of the testis.

Hyper- and Hypothyroidism

Thyroid abnormalities are a rare cause (0.5%) of male infertility. Abnormally high or low levels of serum thyroid hormone impact spermatogenesis at the level of both the pituitary and testis. Euthyroidism is important for normal hypothalamic hormone secretion and for normal sex hormone–binding protein levels that govern the testosterone–estrogen ratio.

Testicular

Many conditions that cause infertility act at the testicular level (Table 44–12.) Unlike many pretesticular conditions, which are treatable with hormonal manipulation, testicular defects are mostly irreversible.

Common Genetic Causes

Y Chromosome Microdeletions

Approximately 7% of men with low sperm counts and 13% of men with azoospermia have a structural alteration in the long arm of the Y chromosome (Yq). The testis-determining region genes that control testis differentiation are intact, but there may be gross deletions in other regions that may lead to defective spermatogenesis. The recent explosion in molecular genetics has allowed for sophisticated analysis of the Y chromosome. At present, three gene sites are being investigated as putative AZF (azoospermia factor) candidates: AZFa, b, and c. The most promising site is AZFc, which contains the DAZ gene region. The gene, of which there are at least six copies in this region, appears to encode a ribonucleic acid (RNA)-binding protein that regulate the meiotic pathway during germ cell production. Homologs of the DAZ gene are found in many other animals, including mouse and Drosophila. A quantitative polymerase chain reaction–based assay is used to test blood for these deletions. In the future, sperm DNA may also be tested as part of a semen analysis. Since men with these microdeletions can have sperm in the ejaculate, they are likely to pass them on to offspring if ART is used.

Klinefelter Syndrome

Abnormalities in chromosomal constitution are well-recognized causes of male infertility. In a study of 1263 infertile couples, a 6.2% overall prevalence of chromosomal abnormalities was detected. Among men whose sperm count was <10 million/mL, the prevalence was 11%. In azoospermic men, 21% had significant chromosomal abnormalities. For this reason, cytogenetic analysis (karyotype) of autosomal and sex chromosomal anomalies should be considered in men with severe oligospermia and azoospermia.

Klinefelter syndrome is the most common chromosomal aneuploidy and a common genetic cause of azoospermia, accounting for up to 14% of cases in some series (overall incidence 1:500 males). The classic triad of findings is small, firm testes; gynecomastia; and azoospermia. Some men may present with delayed sexual maturation, increased height, decreased intelligence, varicosities, obesity, diabetes, leukemia, increased likelihood of extragonadal germ cell tumors, and breast cancer (20-fold higher than in normal men). Among men with Klinefelter syndrome, 90% have an extra X chromosome (47,XXY) and 10% are mosaic, with a combination of XXY/XY chromosomes. The testes are usually <2 cm in length and always <3.5 cm; biopsies show sclerosis and hyalinization of the seminiferous tubules with normal numbers of Leydig cells. Hormones usually demonstrate decreased testosterone and frankly elevated LH and FSH levels. Serum estradiol levels may also be elevated. With age, testosterone levels decline, and most men will require androgen replacement therapy both for virilization and for normal sexual function. Paternity with this syndrome is rare but more likely in the mosaic or milder form of the disease. Some men will have limited spermatogenesis, whereby sperm may be retrieved from the testicles and used with ICSI to cause pregnancy.

Other Genetic Causes and Syndromes

XX Male Syndrome

XX male syndrome is a structural and numerical chromosomal condition, a variant of Klinefelter syndrome that presents as gynecomastia at puberty or as azoospermia in adults. Average height is below normal, and hypospadias is common. Male external and internal genitalia are otherwise normal. The prevalence of mental deficiency is not increased. Hormone evaluation shows elevated FSH and LH and low or normal testosterone levels. Testis biopsy reveals absent spermatogenesis with fibrosis and Leydig cell clumping. The most obvious explanation is that sex-determining ratio (SRY), or the testis-determining region, is translocated from the Y to the X chromosome. Thus, testis differentiation is present; however, the genes that control spermatogenesis on the Y chromosome are not similarly translocated, resulting in azoospermia.

XYY Syndrome

The prevalence of XYY syndrome is similar to that of Klinefelter, but the clinical presentation is more variable. Typically, men with 47,XYY are tall, and 2% exhibit aggressive or antisocial behavior. Hormone evaluation reveals elevated FSH and normal testosterone and LH levels. Semen analyses show either oligospermia or azoospermia. Testis biopsies vary but usually demonstrate arrest of maturation or Sertoli-cell-only syndrome.

Noonan Syndrome

Also called male Turner syndrome, Noonan syndrome is associated with clinical features similar to Turner syndrome (45,X). However, the karyotype is either normal (46,XY) or mosaic (X/XY). Typically, patients have dysmorphic features like webbed neck, short stature, low-set ears, wide-set eyes, and cardiovascular abnormalities. At birth, 75% have cryptorchidism that limits fertility in adulthood. If testes are fully descended, then fertility is possible and likely. Associated FSH and LH levels depend on the degree of testicular function.

Myotonic Dystrophy

Myotonic dystrophy is the most common reason for adult-onset muscular dystrophy. In addition to having myotonia, or delayed relaxation after muscle contraction, patients usually present with cataracts, muscle atrophy, and various endocrinopathies. Most men have testis atrophy, but fertility has been reported. Infertile men may have elevated FSH and LH with low or normal testosterone, and testis biopsies show seminiferous tubule damage in 75% of cases. Pubertal development is normal; testis damage seems to occur later in life.

Vanishing Testis Syndrome

Also called bilateral anorchia, vanishing testis syndrome is rare, occurring in 1:20,000 males. Patients present with bilateral nonpalpable testes and sexual immaturity due to the lack of testicular androgens. The testes are lost due to fetal torsion, trauma, vascular injury, or infection. In general, functioning testis tissue must have been present during weeks 14–16 of fetal life, since Wolffian duct growth and Müllerian duct inhibition occur along with appropriate growth of male external genitalia. Patients have eunuchoid body proportions but no gynecomastia. The karyotype is normal. Serum LH and FSH levels are elevated, and serum testosterone levels are extremely low. There is no treatment for this form of infertility; patients receive lifelong testosterone for normal virilization and sexual function.

Sertoli-Cell-Only Syndrome

Sertoli-cell-only syndrome is characterized by the complete absence of germinal cells on histologic examination of testes biopsies from an azoospermic man. Several causes have been proposed, including genetic defects, congenital absence of normal germ cell migration during embryogenesis, and androgen resistance. Clinically, men are normally virilized with smaller than normal testes with normal consistency. Endocrine function of the testes is preserved and testosterone and LH levels are normal; however, FSH levels are usually (90%) elevated. The use of the word “syndrome” implies that no recognized insult has occurred, since gonadotoxins such as ionizing radiation, chemotherapy, and mumps orchitis can also render the testes aplastic of germ cells. There is no known treatment for this condition. In some patients, extensive testis sampling with FNA mapping or multiple biopsies can reveal sperm that can be used for pregnancy with ARTs.

Defective DNA Mismatch Repair

Defective DNA repair has been suspected to play an etiologic role in certain cancers. Data from mice suggest that mutations in genes needed for DNA repair (PMS2, Mlh1) also lead to infertility characterized by meiotic arrest with a pattern of maturation arrest seen in testis pathology. Male infertility characterized by azoospermia and both germ cell maturation arrest and Sertoli-cell-only syndrome has also been described in association with abnormalities in DNA mismatch repair. This provides evidence that certain forms of male infertility could involve the inability to properly repair germline DNA. The relationship between defective DNA repair in infertile men and their risk of cancer as well as the risk of cancer among their biological offspring certainly merits further research.

Gonadotoxins

Radiation

The effects of radiotherapy on sperm production have been well described. Clifton and Bremner (1983) examined the effects of ionizing irradiation on semen quality and spermatogenesis among a population of healthy prisoners in the 1960s. Before a vasectomy, each of the volunteers was exposed to various levels of radiation and found a distinct dose-dependent, inverse relationship between irradiation and sperm count. Sperm count was significantly reduced at 15 cGy, and azoospermia was temporarily induced at 50 cGy. Persistent azoospermia was induced at 400 cGy, without evidence of recovery for a minimum of 40 weeks. In most subjects, sperm counts rebounded to preirradiation levels with cessation of exposure.

Histologic examination of testis tissue after irradiation has shown that spermatogonia are most sensitive to irradiation while Leydig cell mass is relatively preserved. Given the sensitivity of germ cells to irradiation, some studies have focused on the testicular radiation exposure that occurs during radiation therapy for cancer. During abdominal radiation with gonadal shielding, the estimated mean unintended gonadal exposure is approximately 75 cGy. There does not appear to be an increase in congenital birth defects in offspring of irradiated men. Importantly, recent data have suggested that environmental or occupational exposure to electromagnetic radiation may also reduce semen quality.

Drugs

A list of gonadotoxic medications can be found in Table 44–13. These can result in infertility by various mechanisms. Ketoconazole, spironolactone, and alcohol inhibit testosterone synthesis, whereas cimetidine is an androgen antagonist. Recreational drugs such as marijuana, heroin, and methadone are associated with lower testosterone levels. Certain pesticides, like dibromochloropropane, are likely to have estrogen-like activity. Importantly, the gonadotoxic potential of many pharmaceutical and over-the-counter medications is unknown. Therefore, couples should consider discontinuing and unnecessary medication or supplements prior to their attempt to conceive.

Chemotherapies intended for their cytotoxic effects on rapidly dividing cancer cells also have a profound impact on germ cells that are normally dividing at a rapid rate. Spermatogonia are the germ cells most sensitive to cytotoxic chemotherapy. Alkylating agents such as cyclophosphamide, chlorambucil, and nitrogen mustard are the most toxic agents. The effects of chemotherapeutic drugs vary according to dose and duration of treatment, type and stage of disease, age and health of the patient, and baseline testis function. Despite this toxicity, the mutagenic effects of chemotherapy agents do not appear to be significant enough to increase the chance of birth defects or genetic diseases among offspring of treated men. Patients should wait at least 6 months after chemotherapy ends before attempting to conceive.

Systemic Disease

Renal Failure

Uremia is associated with infertility, decreased libido, erectile dysfunction, and gynecomastia. The cause of hypogonadism is controversial and probably multifactorial. Testosterone levels are decreased, and FSH and LH levels can be elevated. Serum prolactin levels are elevated in 25% of patients. Hyperestrogenemia may play a role in hormone axis derangements and impaired spermatogenesis. Medications and uremic neuropathy may cause uremic-related impotence and a decline in libido. Renal transplantation can result in improvement in hypogonadism.

Liver Cirrhosis

Hypogonadism related to liver failure may have various contributing factors. The reason for organ failure is important. Hepatitis is associated with viremia, and associated fevers can affect spermatogenesis. Excessive alcohol intake inhibits testicular testosterone synthesis, independent of its liver effects. Liver failure and cirrhosis are associated with testicular atrophy, impotence, and gynecomastia. Levels of testosterone and its metabolic clearance are decreased; estrogen levels are increased owing to augmented conversion of androgens to estrogens by aromatase. Decreased testosterone levels are not accompanied by proportionate elevations in LH and FSH levels, suggesting that a central inhibition of the HPG axis may accompany liver failure.

Sickle Cell Disease

As mentioned earlier, sickle cell disease can cause pituitary dysfunction, likely due to the sludging of erythrocytes and associated microinfarcts. This same mechanism may also occur in testis tissue and contribute to primary hypogonadism. As a result, spermatogenesis is decreased, accompanied by lower serum testosterone levels.

Diabetes Mellitus

Prolonged diabetes can result in significant cardiovascular disease, as well as peripheral neuropathy. The impact of such disease on erectile and ejaculatory function has been well described. In addition to poor sexual function, neuropathy involving the parasympathetic and sympathetic pelvic plexus can lead to poor contractility of the bladder neck and ejaculatory organs resulting in retrograde or anejaculation.

Defective Androgen Activity

Peripheral resistance to androgens occurs with two basic defects: (1) a deficiency of androgen production through the absence of 5-alpha-reductase and (2) a deficiency in the androgen receptor. In general, these conditions are a consequence of single gene deletions.

5-Alpha-Reductase Deficiency

5-Alpha-reductase deficiency results in normal development of the testes and Wolffian duct structures (internal genitalia) but ambiguous external genitalia. The ambiguity results from an inborn deficiency of the 5-alpha-reductase enzyme that converts testosterone to DHT in androgen-sensitive tissues like the prostate, seminal vesicle, and external genitalia. Thus far, 29 mutations have been described in the culprit enzyme. The diagnosis is made by measuring the ratio of testosterone metabolites in urine and confirmed by finding decreased 5-alpha-reductase in genital skin fibroblasts. Spermatogenesis has been described in descended testes; however, fertility has not been reported in these patients. The lack of fertility may be due largely to functional abnormalities of the external genitalia.

Androgen Receptor Deficiency

Androgen receptor deficiency is an X-linked genetic condition marked by resistance to androgens. The androgen receptor, a nuclear protein, is absent or functionally altered such that testosterone or DHT cannot bind to it and activate target cell genes. Since androgens have no effect on tissues, both internal and external genitalia are affected. Fertility effects depend on the specific receptor abnormality. Some patients are 46,XY males with complete end-organ resistance to androgens. They have female external genitalia with intra-abdominal testes. Testes show immature tubules and the risk of testis cancer is elevated: Tumors will develop in 10–30% of patients without orchiectomy. Fertility is absent. Patients with mild receptor defects may present as normal-appearing infertile men. Spermatogenesis may be present, although impaired. It is unclear exactly how common this occurs in infertile men.

Testis Injury

Orchitis

Inflammation of testis tissue is most commonly due to bacterial infection, termed epididymo-orchitis. Viral infections also occur in the testis in the form of mumps orchitis. Orchitis is observed in approximately 30% of postpubertal males who develop mumps parotitis. Testis atrophy is a significant and frequent result of viral orchitis but is less common with bacterial infections.

Torsion

Ischemic injury to the testis secondary to twisting of the testis on the spermatic cord pedicle is common in prepubertal and early postpubertal boys. When diagnosed and corrected surgically within 6 hours of occurrence, the testis can usually be saved. Torsion may result in inoculation of the immune system with testis antigens that may predispose to later immunological infertility. It recognized that the “normal” contralateral mate of a torsed testis could also exhibit histologic abnormalities. It has not been clearly demonstrated whether this is related to the actual torsion or to an underlying abnormality in testes predisposed to torsion.

Trauma

Trauma to the testis can result in infertility. Because of the unique immunologic status of the testis in the body (ie, it is an immunologically privileged site), trauma to the testis can invoke an abnormal immune response in addition to atrophy resulting from injury. Both may contribute to infertility. Trauma to the testis that results in fracture of the testis tunica albuginea should be surgically explored and repaired to minimize exposure of testis tissue to the body.

Cryptorchidism

Undescended testis is a common urologic problem, observed in 0.8% of boys at 1 year of age. It is considered a developmental defect and places the affected testis at higher risk of developing testicular germ cell cancer. Although the newborn undescended testis is morphologically normal, deterioration in germ cell numbers is often seen by 2 years of age. The contralateral, normally descended testis is also at increased risk of harboring germ cell abnormalities. Thus, males with either unilaterally or bilaterally undescended testes are at risk for infertility later in life. Historically, orchidopexy was performed solely for the purpose of testicle palpation to allow for cancer detection. However, more recent data have shown that when performed prior to puberty, orchidopexy reduces the risk of cancer development. Other data have suggested that early orchidopexy can improve spermatogenesis in cryptorchid boys.

Varicocele

Varicocele is defined as dilated and incompetent veins within the pampiniform plexus of spermatic cord. Varicocele has been described as the most common surgically correctable cause of male subfertility. This is a disease that develops during puberty when both endocrine and exocrine function of the testicle dramatically increases, along with testicular blood flow. Varicocele is only rarely detected in boys <10 years of age. A left-sided varicocele is found in 15% of healthy young men. In contrast, the incidence of a left varicocele in subfertile men approaches 40%. Bilateral varicoceles are uncommon in healthy men (<10%) but are palpated in up to 20% of subfertile men. In general, varicoceles do not spontaneously regress. An accurate physical examination remains the cornerstone of varicocele diagnosis.

Several anatomic features contribute to the predominance of left-sided varicoceles. The left internal spermatic vein is longer than the right and it typically joins the left renal vein at a right angle compared with the oblique insertion of the right spermatic vein into the inferior vena cava. As a result of these characteristics, higher venous pressures fare transmitted to the left spermatic cord veins and result in retrograde reflux of blood.

Varicoceles are associated with testicular atrophy and varicocele correction can reverse atrophy in adolescents. There is strong evidence that the varicocele affects semen quality. Varicocele can cause abnormalities in concentration, motility, and morphology; however, deficits in motility can be the most profound. The finding of semen abnormalities constitutes the most common indication for varicocele surgery in infertile men.

The mechanism by which varicocele exerts an effect on the testicle remains unclear. Several theories have been postulated and it is likely that a combination of effects results in infertility. Pituitary–gonadal hormonal dysfunction, internal spermatic vein reflux of renal or adrenal metabolites, and an increase in hydrostatic pressure associated with venous reflux are also postulated effects of a varicocele. The most intriguing theory of how varicoceles affect testis function invokes an inhibition of spermatogenesis through the reflux of warm corporeal blood around the testis, with disruption of the normal countercurrent heat exchange balance and elevation of intratesticular temperature.

Idiopathic

It has been estimated that nearly half of male infertility has no readily identifiable cause. The etiology of male infertility is likely multifactorial, encompassing genetic, endocrine, and environmental factors. In addition, modifiable lifestyle characteristics may make a significant contribution to the disease. The effects of physical activity, obesity, alcohol and tobacco use, psychological stress, and cell phone usage on male infertility have been examined in a few observational studies, yet results are inconclusive due to limitations in study design.

Posttesticular (Table 44–14)

Reproductive Tract Obstruction

The posttesticular portion of the reproductive tract includes the epididymis, vas deferens, seminal vesicles, and associated ejaculatory apparatus.

Congenital Blockages

Cystic Fibrosis

CF is the most common autosomal recessive genetic disorder in the United States with a carrier frequency of 1:20 among Caucasians. The disease is caused by defective chloride ion transport across cell membranes resulting in fluid and electrolyte abnormalities (abnormal chloride–sweat test). CF typically presents with chronic lung obstruction and pulmonary infections, pancreatic insufficiency, and infertility. More than 95% of men with CF also have congenital bilateral absence of the vas deferens (CBAVD). In addition to the vas, parts of the epididymis, seminal vesicles, and ejaculatory ducts may be atrophic or absent, causing obstruction. Although spermatogenesis is quantitatively normal, recent data suggest that sperm from men with CF may lack the normal capacity to fertilize an egg. Furthermore, some carriers of abnormal CF genes may also have functional sperm defects. CBAVD accounts for 1–2% of infertility cases. On physical examination, no palpable vas deferens is observed on one or both sides. As in CF, the rest of the reproductive tract ducts may also be abnormal and unreconstructable. This disease is related to CF. Even though most of these men demonstrate no symptoms of CF, up to 80% of patients will harbor a detectable CF mutation. In addition, 15% of these men will have renal malformations, most commonly unilateral agenesis.

Young Syndrome

Young syndrome presents with a triad of chronic sinusitis, bronchiectasis, and OA. The obstruction is in the epididymis. The pathophysiology of the condition is unclear but may involve abnormal ciliary function or abnormal mucus quality. Reconstructive surgery is associated with lower success rates than that observed with other obstructed conditions.

Idiopathic Epididymal Obstruction

Idiopathic epididymal obstruction is a relatively uncommon condition found in otherwise healthy men. There is recent evidence linking this condition to CF in that one-third of men so obstructed may harbor CF gene mutations.

Adult Polycystic Kidney Disease

Adult polycystic kidney disease is an autosomal dominant disorder associated with numerous cysts of the kidney, liver, spleen, pancreas, epididymis, seminal vesicle, and testis. Disease onset usually occurs in the twenties or thirties with symptoms of abdominal pain, hypertension, and renal failure. Infertility with this disease is usually secondary to obstructing cysts in the epididymis or seminal vesicle.

Blockage of the Ejaculatory Ducts

Blockage of the ejaculatory ducts, the delicate, paired, collagenous tubes that connect the vas deferens and seminal vesicles to the urethra, is termed EDO. It is the cause of infertility in 5% of azoospermic men. Obstruction can be congenital and result from Müllerian duct (utricular) cysts, Wolffian duct (diverticular) cysts, or congenital atresia or is acquired from seminal vesicle calculi or postsurgical or inflammatory scar tissue. It presents as hematospermia, painful ejaculation, or infertility. The diagnosis is confirmed by finding a low-volume ejaculate and TRUS showing dilated seminal vesicles or dilated ejaculatory ducts.

Acquired Blockages

Vasectomy

Vasectomy is performed on more than ½ million men per year in the United States for contraception. Subsequently, 6% of these men have the vasectomy reversed, most commonly because of remarriage.

Groin and Hernia Surgery

Groin and hernia surgery can result in inguinal vas deferens obstruction in 1% of cases. There has been concern that Marlex mesh used for hernia repairs may add to perivasal inflammation and increase the likelihood of vassal obstruction.

Bacterial Infections

Bacterial infections (E. coli in men age >35 or Chlamydia trachomatis in young men) may involve the epididymis, with scarring and obstruction.

Functional Blockages

Besides physical obstruction, functional obstruction of the seminal vesicles may exist. Functional blockages may result from nerve injury or medications that impair the contractility of seminal vesicle or vasal musculature. A classic example of nerve injury affecting ejaculation is after retroperitoneal lymph node dissection for testis cancer. This can cause either retrograde ejaculation or complete anejaculation, depending on the degree of injury to postganglionic sympathetic fibers arising from the thoracolumbar spinal cord. These autonomic nerves overlie the inferior aorta and coalesce as the hypogastric plexus within the pelvis and control seminal emission. Multiple sclerosis and diabetes are other conditions that result in disordered ejaculation.

Evidence from animal models indicates that the seminal vesicles possess contractile properties similar to those of the urinary bladder, suggesting that seminal vesicle organ dysfunction may underlie some cases of ejaculatory duct “obstruction.” Medications implicated in this functional problem are those classically associated with ejaculatory impairment. Table 44–5 lists these medications.

Disorders of Sperm Function or Motility

Immotile Cilia Syndromes

Immotile cilia syndromes are a heterogeneous group of disorders (1:20,000 males) in which sperm motility is reduced or absent. The sperm defects are due to abnormalities in the motor apparatus or axoneme of sperm and other ciliated cells. Normally, nine pairs of microtubules are organized around a central microtubule pair within the sperm tail and are connected by dynein arms (ATPase) that regulate microtubule and therefore sperm tail motion. Various defects in the dynein arms cause deficits in ciliary and sperm activity. Kartagener syndrome is a subset of this disorder (1:40,000 males) that presents with the triad of chronic sinusitis, bronchiectasis, and situs inversus. Most immotile cilia cases are diagnosed in childhood with respiratory and sinus difficulties. Cilia present in the retina and ear may also be defective and lead to retinitis pigmentosa and deafness in Usher's syndrome. Men with immotile cilia characteristically have nonmotile but viable sperm in normal numbers. The diagnosis can only be confirmed with electron microscopy of sperm.

Immunologic Infertility

Autoimmune infertility has been implicated as a cause of infertility in 10% of infertile couples. The testis is an immunologically privileged site, probably owing to the blood–testis barrier, which consists of Sertoli cell tight junctions and locally downregulated cellular immunity. Autoimmune infertility may result from an abnormal exposure to sperm antigens as the result of vasectomy, testis torsion, or biopsy, which then incites a pathologic immune response. Antibodies may disturb sperm transport or disrupt sperm–egg interaction. Many assays are available to detect ASAs, but assays that detect sperm-bound, and not serum, antibodies are the most clinically relevant.

Infection

The agents most commonly responsible for male genital tract infections are listed in Table 44–10. Various products of activated leukocytes can exist in infected semen. A correlation exists between leukocytes in semen and the generation of superoxide anions, hydrogen peroxide, and hydroxyl radicals (reactive oxygen species), all of which can damage sperm membranes. Sperm are highly susceptible to the effects of oxidative stress because they possess little cytoplasm and therefore little antioxidant activity. Damage to sperm from oxidative stress has been correlated to loss of function and damaged DNA. Although genital tract infection has been linked to infertility in epidemiologic studies, the correlation between individual organisms and infertility is unclear. Uncontrolled studies suggest that pregnancy rates may improve after treatment, but controlled studies do not confirm these findings.

Disorders of Coitus

Impotence

Sexual dysfunction stemming from low libido or impotence is a frequent cause of infertility. The male hormonal evaluation can detect organic reasons for such problems. Most cases of situational impotence, in which the stress of attempting to conceive results in poor erections, are treated with sexual counseling and oral phosphodiesterase inhibitors.

Hypospadias

Anatomic problems like hypospadias can cause inappropriate placement of the seminal coagulum too distant from the cervix and result in infertility.

Timing and Frequency

Simple problems of coital timing and frequency can be corrected by a review of the couple's sexual habits. An appropriate frequency of intercourse is every two days, performed within the periovulatory period, the window of time surrounding ovulation when egg fertilization is possible. Charting of basal body temperature by the female partner allows for the calculation of that period for the next ovulatory cycle. Home kits that detect the LH surge in the urine before ovulation are also helpful. Couples should be counseled to avoid lubricants if at all possible. It is also wise to discontinue any unnecessary medications during attempts to conceive. Other coital toxins include heat exposure from regular saunas, hot saunas, hot tubs, or Jacuzzis and the use of cigarettes, cocaine, marijuana, and excessive alcohol.

Surgical Treatments

The role of surgery in the treatment of certain causes of male infertility is well established and cost-effective when compared with high-technology approaches. Surgeries that attempt to reverse specific anatomic or pathophysiologic defects may result in normalization or improvement in semen quality, thus allowing a couple to conceive naturally rather than the use of ART. Other surgeries are for the purpose of obtaining sperm directly from the testis or epididymis and are intended to be used in conjunction with ART.

Varicocele

The association of varicoceles with male infertility is well established. Several treatment modalities, both surgical and nonsurgical, are available for varicoceles. These include ligation of the veins through the retroperitoneal, inguinal, or subinguinal approaches; percutaneous embolization; and laparoscopy. The common goal of all treatments is to stop the retrograde flow of venous blood through the internal spermatic veins. Treatments can be compared in terms of expected success rates (semen improvement and pregnancy), cost, and outcomes (pain pills, return to work or other activity), and their relative merits can be analyzed. A basic comparison of three treatment options is outlined in Table 44–15. Remember that if watchful waiting is chosen, a pregnancy rate of 16% can be expected. If IVF is chosen, a pregnancy rate of 35% can be expected. An overall complication rate of 1% is associated with the incisional approach, compared with a 4% complication rate for laparoscopy and 10–15% for radiologic occlusion. A significant problem with the radiologic approach is technical failure, meaning the inability to access and occlude the spermatic vein.

Vasectomy Reversal

More than 500,000 men per year undergo vasectomy in the United States, and nearly 6% will eventually wish to have their vasectomy reversed. The most common reasons relate to changes in a man's social circumstances and include remarriage and the loss of a child. Causes of vasal obstruction other than vasectomy include infection, congenital, trauma, and previous surgery and are less frequent indications for vasovasostomy or epididymovasostomy. A problem with duct obstruction should be suspected in men with normal testis size, normal hormones, and azoospermia.

Several methods have been described for vasovasostomy. None has been proved superior to any other, except that magnification with an operating microscope results in better success rates. In general, either a single-layer anastomosis or a double-layer anastomosis is performed (Figure 44–13). Although these procedures are technically different, the experience of the surgeon is the most important factor for success. Depending on these factors, 95% or more of patients may have a return of sperm after a vasovasostomy. If vasal fluid below the level of the vasectomy does not contain sperm, there may be a secondary obstruction in the epididymis. Such obstruction may result from rupture of the epididymal tubules in response to increased luminal pressure. A prolonged period of vasectomy or a vasectomy close to the epididymis increases the risk of an epididymal blockage. In this case, the vas must be connected to the epididymis above the area of rupture in an operation called an epididymovasostomy. Although this is a technically challenging operation, given improvements in surgical techniques and instrumentation, approximately 60–65% of men will have sperm in the ejaculate following epididymovasostomy.

The achievement of sperm in the ejaculate after vasovasostomy depends largely on surgical technique, but pregnancy after surgery is dependent upon the fertility potential of the couple. Therefore, it is critical to understand the reproductive health of the female partner before embarking on the procedure. Other reasons that reproductive tract microsurgery fails are (1) the quality of preblockage semen may not have been normal; (2) ASAs develop in roughly 30% of men who have had vasectomies (high antibody levels may impair fertility); (3) postsurgical scar tissue can develop at the anastomotic site, causing another blockage; (4) when the vas deferens has been blocked for a long time, the epididymis is adversely affected and sperm maturation may be compromised.

Ejaculatory Duct Obstruction

EDO should be suspected when the ejaculate volume is <1.5 mL and no retrograde ejaculation or hormonal deficit has been identified. EDO can take several forms (Table 44–16). Complete or classic EDO is the physical blockage of both ejaculatory ducts and presents with low-volume azoospermia. Incomplete or “partial” EDO is the unilateral, physical blockage of one of the paired ducts or the partial blockage of both ducts. This condition is generally associated with low ejaculate volume and low sperm concentrations and severely impaired motility. Functional EDO is a form of ejaculatory dysfunction that presents as classic EDO but without anatomical evidence of physical blockage. Clinical suspicion can be confirmed by TRUS demonstration of dilated seminal vesicles or dilated ejaculatory ducts. Patients with EDO sufficient to cause coital discomfort, recurrent hematospermia, or infertility should be considered for treatment.

Transurethral resection of the ejaculatory ducts (TURED) is performed cystoscopically (Figure 44–14). A small resectoscope is inserted, and the verumontanum is resected in the midline until the ducts are visualized. The concomitant use of real-time TRUS may increase the accuracy of resection. Since the area of resection is at the prostatic apex, near the external urethral sphincter and the rectum, careful positioning of the resectoscope is essential. Sixty-five to seventy percent of men show significant improvement in semen quality after TURED and a 30% pregnancy rate can be expected. The complication rate from TURED is approximately 20%. Most complications are self-limited and include hematospermia, hematuria, urinary tract infection, epididymitis, and a watery ejaculate. Rarely reported complications include retrograde ejaculation, rectal perforation, and urinary incontinence.

Electroejaculation

A complete failure of emission and ejaculation occurs most commonly from spinal cord injury (10,000 cases/year in the United States) and as a result of deep pelvic or retroperitoneal surgery that injured the pelvic sympathetic nerves. With rectal probe electroejaculation, the pelvic sympathetic nerves undergo controlled stimulation, with contraction of the vas deferens, seminal vesicle, and prostate, such that a reflex ejaculation is induced. The semen is collected from the penis and the bladder as retrograde ejaculation is often associated with electroejaculation. Semen acquired in this way at minimum requires the use of IUI to allow for pregnancy.

In men with anejaculation after retroperitoneal surgery or spinal trauma, successful recovery of sperm with electroejaculation is possible in the majority of patients. Sperm motility tends to be lower than normal when obtained in this way, an effect independent of electrical or heat effects inherent to the procedure. In men with spinal cord injuries above the T5 level, it is often possible to induce a reflex ejaculation with high-frequency penile vibration, termed vibratory stimulation. With the use of handheld vibrators set to a frequency of 110 cycles/s at an amplitude of 3 mm, patients may be taught to perform the procedure and attempt to conceive at home with cervical insemination.

Sperm Retrieval

Sperm retrieval techniques are indicated for men in whom ejaculation of sperm is not possible because the ductal system is absent, surgically unreconstructable, or because the couple has elected to use ART rather than vasectomy reversal. Testicular sperm retrieval is also indicated in men with NOA who may harbor areas of reduced spermatogenesis within the testes. Given these widely varied indications, retrieval techniques have evolved to include minimally invasive aspiration procedures and more invasive dissections of the testis with the aid of an operating microscope. Sperm are routinely aspirated from the vas deferens, epididymis, or testicle. It is important to realize that IVF is required to achieve a pregnancy with these procedures. Thus, success rates are intimately tied to a complex program of assisted reproduction for both partners (Table 44–17). In cases of sperm aspiration from the testicle and epididymis, IVF along with ICSI is required. An obvious prerequisite for these procedures is sperm production. Although evaluated indirectly by hormone levels and testis volume, the most direct way to verify sperm production is with a testis biopsy.

Vasal Aspiration

After a scrotal incision and with an operating microscope, a hemivasotomy is made, and leaking sperm are aspirated into culture medium. Once enough sperm are obtained (>10–20 million), the vasotomy is closed with microscopic sutures. Vasal aspiration provides the most mature sperm.

Epididymal Sperm Aspiration

Epididymal sperm aspiration may be performed by two distinct techniques. With microscopic epididymal sperm aspiration (MESA), sperm are directly collected from a single, isolated epididymal tubule (Figure 44–15). After sperm are obtained, the epididymal tubule is closed with fine, microscopic suture, and the sperm are processed. When the epididymis is palpable, sperm may also be obtained with percutaneous epididymal sperm aspiration (PESA). Although this technique is a less invasive, the blind insertion of a needle into the epididymis may be more likely to result in tubule injury, thus reducing the chances for successful subsequent vasectomy reversal. Epididymal sperm are not as mature as vasal sperm; as a consequence, epididymal sperm require ICSI to fertilize the egg. Egg fertilization rates of 65% and pregnancy rates of 50% are possible with epididymal sperm, but results vary among individuals because of differences in sperm and egg quality.

Testis Sperm Retrieval

Testicular sperm extraction (TESE) is indicated for patients in whom there is an unreconstructable blockage in the epididymis, or in cases of severe testis failure, in which so few sperm are produced that they cannot reach the ejaculate. Testicular sperm retrieval procedures are highly variable in terms of their surgical invasiveness. Whenever possible, the least invasive approach necessary to acquire adequate sperm should be used. In traditional TESE, a small piece of testis tissue is taken in a manner similar to that of a regular testis biopsy. When spermatogenesis is known or suspected to be normal, or is reduced but uniformly distributed throughout the testicle, then testicular sperm aspiration (TESA) should be considered. In distinction to this, if spermatogenesis is markedly reduced, as in many cases of NOA, the greatest changes for successful sperm retrieval will achieved by meticulously dissecting all testicular tissue with the aid of a surgical microscope (micro-TESE). The testis tissue is specially treated in the laboratory to separate sperm from other cells. High egg fertilization rates (60–75%) and pregnancy rates (40–50%) are possible with testis sperm despite the fact that normal motility is usually lacking.

Orchidopexy

An undescended testis occurs in 0.8% of male infants at 1 year of age and the incidence may be increasing. Historically, orchidopexy was done to allow for palpation of a testis that was at increased risk for cancer. More recent evidence suggests that early orchidopexy reduces cancer risk and may improve spermatogenesis later in life. Histologic studies of undescended testis show that significant decreases in spermatogonial numbers occur between birth and 2 years of age. Orchidopexy has been recommended within 2 years of age to potentially prevent this germ cell degeneration. Given that sperm can be retrieved from very atrophic testes and used with assisted reproduction, orchidopexy and not orchiectomy should be the primary goal in these cases.

Torsion of the testis is a urologic emergency. Data from animal studies suggest that the unaffected, contralateral testis may also develop impaired spermatogenesis termed sympathetic orchidopathia. This phenomenon may be immunologic in nature and is the basis for the recommendation that a nonviable torsed testicle be removed at diagnosis. However, given the advances in ARTs, such recommendations should be reconsidered.

Pituitary Ablation

Hyperprolactinemia from a pituitary adenoma can be treated medically and surgically. If the adenoma is radiologically visible (macroadenoma), then transsphenoidal surgical ablation of the lesion is possible. If the adenoma is not visible (microadenoma), then medical therapy with the dopamine agonist bromocriptine or a derivative is more appropriate. Studies have suggested that hyperprolactinemia alone independent of gonadotropin deficiencies can suppress normal testicular function.

Nonsurgical Treatments

Specific Therapy

Specific therapy refers to treatments aimed at reversing known pathophysiology in an effort to improve spermatogenesis and fertility. These therapies should be contrasted to empiric therapies that aim to overcome a pathologic condition. Whenever possible, specific therapies should be elected over empiric therapies.

Leukocytospermia

Elevated leukocytes in semen is termed leukocytospermia and has been associated with (1) subclinical genital tract infection, (2) elevated reactive oxygen species, and (3) poor sperm function and infertility. The treatment of leukocytospermia is controversial in the absence of overt bacteriologic infection. It is important to evaluate the patient for sexually transmitted diseases, penile discharge, prostatitis, or epididymitis. An expressed prostatic secretion is examined for leukocytes; urine can be assayed for chlamydial, gonococcal, and mycoplasma infections. The use of broad-spectrum antibiotics such as doxycycline and trimethoprim–sulfamethoxazole may reduce seminal leukocyte concentrations or improve sperm function; however, this remains a debated topic. In general, the female partner is also treated. Importantly, the histologic appearance of immature germ cells can be confused with leukocytes in a semen sample. Therefore, is critical to avoid treating leukocytospermia purely on the basis of elevated “round cells.” Specific staining for leukocyte esterase with a concentration of cells greater than one million per milliliter confirms the diagnosis.

In cases of confirmed leukocytospermia, frequent ejaculation (more than every 3 days) and doxycycline may result in a more durable resolution than antibiotic treatment alone. There is increasing evidence that the antioxidant vitamins (A, C, and E) as well as glutathione and Omega-3 fatty acids (fish oil) may help scavenge reactive oxygen species within semen and improve sperm motility in cases of leukocytospermia.

Coital Therapy

Simple counseling on issues of coital timing, frequency, and gonadotoxin avoidance can improve fertility. It is important to review the essentials of basal body temperature charting or home kits that detect the LH surge in the urine immediately (<24 hours) before ovulation. Since sperm reside in the cervical mucus for 48 hours and are released continuously, it is not necessary that coitus and ovulation occur at the exact same time. In general, coitus every other day around ovulation is an appropriate recommendation. Coital lubricants should be avoided if possible, as many commercially available products are toxic to sperm. If necessary, vegetable oils, olive oil, and egg whites are the safest.

Retrograde ejaculation results from a failure of the bladder neck to close during ejaculation. Diagnosed by the finding of sperm within the postejaculate bladder urine, it can be treated with sympathomimetic medications. Approximately 30% of men will respond to treatment with some degree of antegrade ejaculation. Begun several days before ejaculation, imipramine (25–50 mg twice a day), or Sudafed Plus (60 mg three times a day), has been used with success. For medication failure, sperm harvesting techniques can be used with IUI to achieve a pregnancy. Premature ejaculation occurs when men ejaculate before the partner is ready. Sexual counseling combined with tricyclic antidepressants or serotoninergic uptake inhibitors can be effective.

Immunologic Infertility

ASAs are a complex problem underlying male infertility. Available treatment options include corticosteroid immune suppression, sperm washing, IUI, IVF, and ICSI. Steroid suppression is based on the concept that the immune system can be weakened to reduce antibodies on sperm; however, this modality is rarely used given the potential for significant side effects. IUI places more sperm nearer the ovulated egg to optimize the sperm–egg environment. Pregnancy rates with this technique generally fall in the 10–15%/cycle range. ART with IVF and ICSI is very effective in this scenario. In general, if >50% of sperm are bound with antibodies, then treatment should be offered. In addition, head-directed or midpiece-directed sperm antibodies appear more relevant than tail-directed antibodies.

Medical Therapies

Hormone therapy is effective when it is used as specific and not empiric treatment. Specific replacement therapy seeks to reverse well-established, pathophysiologic states. Empiric treatments attempt to overcome pathologic conditions that are ill defined or have no proven treatment.

Hyperprolactinemia

Normal levels of prolactin in men help sustain high intratesticular testosterone levels and affect the growth and secretions of the accessory sex glands. Hyperprolactinemia abolishes gonadotropin pulsatility by interfering with episodic GnRH release. Visible lesions are generally treated with transsphenoidal surgery, and nonvisible lesions are treated with bromocriptine, 5–10 mg daily, to restore normal pituitary balance.

Hypothyroidism

Both elevated and depressed levels of thyroid hormone can impair spermatogenesis. Replacement or removal of low or excessive thyroid hormone is effective treatment for infertility. As these diseases are clinically evident, routine thyroid screening is not recommended for infertility patients.

Congenital Adrenal Hyperplasia

Most commonly, the 21-hydroxylase enzyme is deficient resulting in cortisol deficiency and excess androgen production. The testes fail to mature because of gonadotropin inhibition due to excessive androgens. The diagnosis is rare and classically presents as precocious puberty; careful laboratory evaluation is essential. In both sexes, the condition and the infertility associated with it are treated with corticosteroids.

Testosterone Excess/Deficiency

Patients with Kallmann syndrome lack GnRH that stimulates normal pituitary function. Infertility associated with this condition can be very effectively treated with hCG, 1000–2000 U three times weekly, and recombinant FSH 75 IU twice weekly, to replace LH and FSH. It is also possible to give GnRH replacement in a pulsatile manner, 25–50 ng/kg every 2 hours, by a portable infusion pump. Individuals with fertile eunuch syndrome or isolated LH deficiency respond well to hCG therapy alone. One can expect to find sperm in the ejaculate beginning 9–12 months after therapy is started. Since injectable drug regimens are long, complex, and costly, it is good practice for men to cryopreserve motile sperm once achieved in the ejaculate. Anabolic steroids are a common and underdiagnosed reason for testicular failure in which excess exogenous testosterone and metabolites depress the pituitary–gonadal axis and spermatogenesis. Initially, the patient should discontinue the offending hormones to allow the return of normal homeostatic balance. Second-line therapy generally consists pituitary stimulation with clomiphene citrate (see later) or with testis stimulation with hCG and FSH as with Kallmann syndrome.

Empiric Medical Therapy

Nearly a quarter of men evaluated for infertility will not have an identifiable cause. Because the pathophysiology is ill defined, this is termed idiopathic infertility. Additionally, other men in whom an abnormality is identified on semen analysis may have no specific target for therapy. Both groups of men are candidates for empiric medical therapy. This form of therapy seeks to overcome pathologic conditions that are ill defined or have no proven treatment. As a rule, it is important to establish a timeline of therapy and decide with the patient when empiric treatment is to be discontinued and other avenues pursued.

Clomiphene Citrate

Clomiphene citrate is a synthetic, nonsteroidal antiestrogen that blocks the action of the normally low levels of estrogen on the male hormone axis resulting in increased secretion of GnRH, FSH, and LH. The enhanced output of these hormones generally increases testosterone production and may improve spermatogenesis. Its use in male infertility treatment is “off-label,” as it is FDA approved only for the treatment of female infertility. Clomiphene therapy is given for idiopathic low sperm count in the setting of low-normal LH, FSH, and testosterone levels. The dose is 12.5–50 mg/day either continuously or with a 5-day rest period each month. Serum gonadotropins and testosterone should be monitored at 3 weeks and the dose adjusted to keep the testosterone level within the normal range. Higher than normal testosterone levels may result in hyperestrogenemia and decreased semen quality. Therapy should be discontinued if no semen quality response is observed in 6 months. Although there have been more than 30 published trials on clomiphene since 1964, only a few include control arms. In general, the results of these studies have been equivocal with regard to the effectiveness of clomiphene citrate as an empiric therapy. Recent data have suggested that treatment of nonobstructive azoospermic men with clomiphene citrate may improve the odds of successful surgical sperm retrieval.

Antioxidant Therapy

There is evidence that up to 40% of infertile men have increased levels of reactive oxygen species in the reproductive tract. These species (OH, O2 radicals, and hydrogen peroxide) can cause lipid peroxidation damage to sperm membranes that leads to deficits in sperm motility and overall function. Treatment with scavengers of these radicals may protect sperm from oxidative damage. Proposed agents have included glutathione, vitamin E, and fish oil. These agents may be useful in a subgroup of infertile men with elevated levels of seminal reactive oxygen species. Unfortunately, well-controlled studies demonstrating the effectiveness of these supplements are small or not available.

Assisted Reproductive Technologies

If neither surgery nor medical therapy is appropriate for male infertility treatment, assisted reproductive techniques can be used to achieve a pregnancy. Generally speaking, ARTs represents the most profound implementation of empiric therapies.

Intrauterine Insemination

IUI represents the least technological of all ARTs and is generally classified separately from in vitro fertilization. IUI involves the placement of a washed pellet of ejaculated sperm beyond the cervix, within the female uterus. The specific indication for IUI is for a cervical factor; if the cervix is bypassed, then pregnancies may ensue. IUI is also used for low sperm quality, for immunologic infertility, and in men with mechanical problems of sperm delivery (eg, hypospadias). IUI is commonly used for idiopathic infertility. There should be at least 5–40 million motile sperm in the ejaculate (volume × concentration × motility) to make this procedure worthwhile. Success rates vary widely and are directly related to female reproductive potential; given this, pregnancy rates of 8–16% per cycle have been reported with IUI as a treatment for male infertility. Success rates are improved if the female partner is treated with medication to stimulate ovulation.

In Vitro Fertilization and ICSI (Figure 44–16)

In vitro fertilization involves controlled ovarian stimulation and ultrasound-guided transvaginal egg retrieval from the ovaries before normal ovulation occurs. Eggs are then combined with washed sperm in petri dishes to allow fertilization to occur. Importantly, significant numbers of postwash, motile sperm (500,000 to 5 million) are necessary for traditional IVF to be successful. In 1992, microscopic injection of a single sperm into the subzonal space of an egg to cause a pregnancy was described. This technology, termed ICSI, has revolutionized the treatment of severe male factor infertility. The sperm requirement for egg fertilization has dropped from hundreds of thousands for IVF to 1 viable sperm for ICSI. This has led to the development of aggressive new surgical techniques to provide sperm for egg fertilization from men with azoospermia. The availability of these techniques has pushed urologists to look beyond the ejaculate and into the male reproductive tract to find sperm for biologic pregnancies. At present, sources of sperm include the vas deferens, epididymis, and testicle. Since IVF and ICSI eliminate many natural selection barriers that exist during natural fertilization, genetic defects that caused the infertility are expected to be passed on to offspring. Because ICSI is a relatively new technique, long-term data concerning future health and fertility of children conceived with ICSI is not yet available. Some studies have reported the increased incidence of hypospadias in babies conceived through ICSI. Furthermore, because some causes of male infertility are familial and related to genetic problems (Y microdeletions), male offspring may also suffer from impairments in spermatogenesis, inherited from their fathers.

Preimplantation Genetic Diagnosis

Preimplantation genetic diagnosis is a specialized technique that enables the laboratory to precisely define the genetic normality of embryos. In patients with heritable, possibly life-threatening, diseases, it is possible that offspring conceived with IVF and ICSI may have these diseases transmitted to them. This complex technique involves the removal of single cells from the early embryo while it is grown in petri dishes before transfer to the uterus. The genetic material from these “biopsied” cells can then be examined to determine whether the embryo carries an abnormal chromosome or gene. Through preimplantation genetic diagnosis, early human embryos that result from IVF and ICSI can be individually examined as they develop for the presence or absence of suspected genetic traits. Because of the real-time nature of the technique, decisions regarding embryo transfer are made within 24 hours and help ensure that lethal diseases are not transmitted to offspring. Remarkably, the removal of a few cells from the embryo is not detrimental to the survival and normal development of most embryos.

Nonreproductive Implications of Male Infertility

Beyond the significant psychosocial and marital stress, which is associated with male infertility, several epidemiologic studies have suggested that male infertility may be a marker for overall health. A large, longitudinal Danish study suggested that male fertility may be associated with overall longevity, whereby men with better semen quality may have lower age-adjusted mortality than men with worse semen quality. Other studies have demonstrated that male infertility is a strong risk factor for the development of testicular germ cell cancer later in life. A large US cohort study found that infertile men were nearly three times more likely to develop testis cancer, and on average, men presented with infertility more than a decade prior to developing cancer. Other studies have suggested that male subfertility may be risk factor for prostate cancer; however, these studies have yet to be confirmed and further investigation is warranted. While male infertility and its treatments are unlikely to be causative with regard to cancer, it is highly likely that these diseases share a common underlying etiology. Given that men present with reproductive failure relatively early in life, the epidemiologic study of infertile men may provide the opportunity to identify and remove exposure to carcinogenic agents.

Bibliography