Male Infertility

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Practice Essentials

Infertility in men can result from deficiencies in sperm formation, concentration, or transportation. This general division allows an appropriate workup of potential underlying causes of infertility and helps define a course of action for treatment.

The image below depicts male ductal anatomy.



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Male infertility. Normal male ductal anatomy.

Signs and symptoms

The initial step in the evaluation of an infertile male is to obtain a thorough medical and urologic history. Such a history should include consideration of the following:

The physical examination should include a thorough inspection of the following:

Depending on the findings from the history, detailed examination of other body functions may also be warranted.

See Presentation for more detail.

Diagnosis

The semen analysis is the cornerstone of the male infertility workup and includes assessment of the following:

Other laboratory tests that may be helpful include the following:

Imaging studies employed in this setting may include the following:

An abnormal postcoital test result is observed in 10% of infertile couples. Indications for performing a postcoital test include semen hyperviscosity, increased or decreased semen volume with good sperm density, or unexplained infertility.

If the test result is normal, consider sperm function tests, such as the following:

Testicular biopsy is indicated in azoospermic men with a normal-sized testis and normal findings on hormonal studies to evaluate for ductal obstruction, to further evaluate idiopathic infertility, and to retrieve sperm.

See Workup for more detail.

Management

The following causes of infertility, if identified, can often be treated by medical means:

Surgical interventions to be considered include the following:

See Treatment and Medication for more detail.

Background

Infertility is defined as the inability to achieve pregnancy after one year of unprotected intercourse. An estimated 15% of couples meet this criterion and are considered infertile, with approximately 35% due to female factors alone, 30% due to male factors alone, 20% due to a combination of female and male factors, and 15% unexplained. Conditions of the male that affect fertility are still generally underdiagnosed and undertreated.

Causes of infertility in men can be categorized as obstructive or nonobstructive. Infertile men may have deficiencies in sperm formation, concentration (eg, oligospermia [too few sperm], azoospermia [no sperm in the ejaculate]), or transportation. This general division allows an appropriate workup of potential underlying causes of infertility and helps define a course of action for treatment.

The initial evaluation of the male patient should be rapid, noninvasive, and cost-effective, as nearly 70% of conditions that cause infertility in men can be diagnosed with history, physical examination, and hormonal and semen analysis alone. More detailed, expensive, and invasive studies can then be ordered if necessary.

Treatment options are based on the underlying etiology and range from optimizing semen production and transportation with medical therapy or surgical procedures to complex assisted reproduction techniques. Technological advancements have made conceiving a child possible with as little as one viable sperm and one egg.[1] Although the workup was traditionally delayed until a couple was unable to conceive for 12 months, evaluation may be initiated at the first visit in slightly older couples.

Pathophysiology

Gonadal and sexual functions are mediated by the hypothalamic-pituitary-gonadal axis, a closed-loop system with feedback control from the testicles. The hypothalamus, the primary integration center, responds to various signals from the central nervous system (CNS), pituitary gland, and testicles to secrete gonadotropin-releasing hormone (GnRH) in a pulsatile pattern approximately every 70-90 minutes. The half-life of GnRH is 2-5 minutes.

Release of GnRH is stimulated by melatonin from the pineal gland and inhibited by testosterone, inhibin, corticotropin-releasing hormone, opiates, illness, and stress. GnRH travels down the portal system to the anterior pituitary, located on a stalk in the sella turcica, to stimulate the release of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). See the image below.



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Male infertility. Hypothalamic-pituitary-gonadal axis stimulatory and inhibitory signals. Gonadotropin-releasing hormone (GnRH) from the hypothalamus ....

FSH and LH, glycopeptides with a molecular weight of 10,000 Daltons, are each composed of an alpha chain that is identical to that of human chorionic gonadotropin (hCG) and thyroid-stimulating hormone (TSH), but with a beta chain that is unique for each. FSH has a lower plasma concentration and longer half-life than LH, and it has less obvious pulsatile changes. The pulsatile nature of GnRH is essential to normal gonadotropin release; a continuous stimulation inhibits their secretion.

The hypothalamus also produces thyrotropin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP), both of which stimulate prolactin release from the anterior pituitary, and dopamine, which inhibits prolactin release. Men with elevated prolactin levels present with gynecomastia, diminished libido, erectile dysfunction, and occasionally galactorrhea. Prolactin inhibits the production of GnRH from the hypothalamus and LH and FSH from the pituitary. Gonadotropin release is modulated by various other signals, such as estradiol (a potent inhibitor of both LH and FSH release), and inhibin from the Sertoli cell, which causes a selective decrease in FSH release.

FSH and LH are released into the systemic circulation and exert their effect by binding to plasma membrane receptors of the target cells. LH mainly functions to stimulate testosterone secretion from the Leydig cells of the testicle, while FSH stimulates Sertoli cells to facilitate germ cell differentiation.

Testosterone is secreted in a diurnal pattern, peaking a few hours after the man awakens from sleep. In the body, testosterone circulates 2% in the free form, 44% bound to sex hormone–binding globulin (SHBG), and 54% bound to albumin. Testosterone is converted to dihydrotestosterone (DHT) by the action of 5-alpha reductase, both locally and in the periphery, and to estrogen in the periphery. Testosterone and estradiol function as feedback inhibitors of gonadotropin release.

The testicle contains the Leydig cells and the Sertoli cells and is covered by the tunica albuginea, which also provides septae that divide it into approximately 200-350 pyramids (see image below). These pyramids are filled with the seminiferous tubules. A normal testicle contains 600-1200 seminiferous tubules with a total length of approximately 250 meters. The interstitium between the seminiferous tubules contains the Leydig cells, fibroblasts, lymphatics, blood vessels, and macrophages. Histologically, Leydig cells are polygonal with eosinophilic cytoplasm. Occasionally, the cytoplasm contains crystalloids of Reinke after puberty.



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Male infertility. Testicular histology magnified 500 times. Leydig cells reside in the interstitium. Spermatogonia and Sertoli cells lie on the baseme....

Seminiferous tubules are made up of Sertoli cells and germ cells and are surrounded by peritubular and myoid cells.

Sertoli cells are columnar, with irregular basal nuclei that have prominent nucleoli and fine chromatin. They rest on the basement membrane and serve mainly to support, nourish, and protect the developing germ cells and to provide a blood-testis barrier to provide a microenvironment that facilitates spermatogenesis and maintains the germ cells in an immunologically privileged location. Sertoli cells also secrete inhibin, which provides negative feedback on the hypothalamus, and androgen-binding protein, which helps modulate androgen activity in the seminiferous tubules. In addition to stimulation by FSH, Sertoli cell function is modulated by intratesticular testosterone and signals from peritubular myoid cells.

Germ cells (precursors to spermatozoa) are derived from the gonadal ridge and migrate to the testicle before testicular descent. In response to FSH stimulation at puberty, germ cells become spermatogonia and undergo an ordered maturation to become spermatozoa. The entire process of development from spermatogonium to spermatid takes 74 days and is described in 14 steps; as they mature, the developing spermatids progress closer to the lumen of the seminiferous tubule.

Spermatogonia rest on the basement membrane and contain dense nuclei and prominent nucleoli. Three types are described: A dark (Ad), A pale (Ap), and B cells. Ad cells (stem cells) divide to create more Ad cells (stem cell renewal) or differentiate into daughter Ap cells every 16 days. Ap cells mature into B spermatogonia, which then undergo mitotic division to become primary spermatocytes, which are recognized by their large centrally located nuclei and beaded chromatin. The mitotic division does not result in complete separation; rather, daughter cells maintain intracellular bridges, which have functional significance in cell signaling and maturation.

Primary spermatocytes undergo meiosis as the cells successively pass through the preleptotene, leptotene, zygotene, and pachytene stages to become secondary spermatocytes. During this time, the cells cross from the basal to the adluminal compartments. Secondary spermatocytes contain smaller nuclei with fine chromatin. The secondary spermatocytes undergo a second meiosis and become spermatids. This reduction division (ie, meiosis) results in a haploid chromosome number. Therefore, a total of 4 spermatids are made from each spermatocyte.

Next, the spermatids undergo the process of spermiogenesis (through stages named Sb1, Sb2, Sc, Sd1, and Sd2), which involves the casting of excess cytoplasm away as a residual body, the formation of the acrosome and flagella, and the migration of cytoplasmic organelles to their final cellular location. The acrosome, a derivative of the Golgi process, surrounds the nucleus anteriorly and contains enzymes necessary to penetrate the ovum. The mature spermatid is then located adjacent to the tubule lumen and contains dark chromatin with an oval-shaped nucleus.

After their release from the Sertoli cells into the lumen of the seminiferous tubules, the spermatids successively pass through the tubuli recti, rete testis, ductuli efferentes, and, finally, the epididymis (see image below). The epididymis is a 3- to 4-cm long structure with a tubular length of 4-5 m. As sperm move from the head to the tail, they mature and acquire fertilization capacity. Sperm from the head move with immature wide arcs and are generally unable to penetrate the egg, while those from the tail propel forward and have better penetration capacity. The transit time varies with age and sexual activity but is usually from 1-12 days. The epididymis additionally secretes substances for sperm nutrition and protection such as glycerophosphorylcholine, carnitine, and sialic acid.



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Male infertility. Normal male ductal anatomy.

Sperm next enter the vas deferens, a 30- to 35-cm muscular conduit of Wolffian duct origin. The vas is divided into the convoluted, scrotal, inguinal, retroperitoneal, and ampullary regions and receives its blood supply from the inferior vesical artery. In addition to functioning as a conduit, the vas also has absorptive and secretory properties.

During emission, sperm are propelled forward by peristalsis. After reaching its ampullary portion behind the bladder, the vas joins with the seminal vesicles, at the ejaculatory duct, which empties next to the verumontanum of the prostate.

During ejaculation, the ejaculate is propelled forward by the rhythmic contractions of the smooth muscle that surrounds the ducts and by the bulbourethral muscles and other pelvic muscles. Bladder neck closure during ejaculation is vital to ensure antegrade ejaculation.

Normal ejaculate volume ranges from 1.5 to 5 mL and has a pH level of 7.05-7.8. The seminal vesicles provide 40-80% of the semen volume, which includes fructose for sperm nutrition, prostaglandins and other coagulating substances, and bicarbonate to buffer the acidic vaginal vault. Normal seminal fructose concentration is 120-450 mg/dL, with lower levels suggesting ejaculatory duct obstruction or absence of the seminal vesicles.

The prostate gland contributes approximately 10-30% (0.5 mL) of the ejaculate. Products include enzymes and proteases to liquefy the seminal coagulum. This usually occurs within 20-25 minutes. The prostate also secretes zinc, phospholipids, phosphatase, and spermine. The testicular-epididymal component includes sperm and comprises about 5% of the ejaculate volume.

In addition to the components already listed, semen is also composed of secretions from the bulbourethral (Cowper) glands and the (periurethral) glands of Litre, each producing 2-5% of the ejaculate volume, serving mainly to lubricate the urethra and to buffer the acidity of the residual urine. The ordered sequence of release is important for appropriate functioning.

For conception, sperm must reach the cervix, penetrate the cervical mucus, migrate up the uterus to the fallopian tube, undergo capacitation and the acrosome reaction to digest the zona pellucida of the oocyte, attach to the inner membrane, and release its genetic contents within the egg. The cervical mucus changes consistency during the ovulatory cycle, being most hospitable and easily penetrated at mid cycle. After fertilization, implantation may then take place in the uterus. Problems with any of these steps may lead to infertility.

Frequency

United States

An estimated 10-15% of couples are considered infertile, defined by the World Health Organization (WHO) as the absence of conception after at least 12 months of unprotected intercourse. In US men, the risk correlates to approximately 1 in 25. Low sperm counts, poor semen quality, or both account for 90% of cases; however, studies of infertile couples without treatment reveal that 23% of these couples conceive within 2 years, and 10% more conceive within 4 years. Even patients with severe oligospermia (< 2 million sperm/mL) have a 7.6% chance of conception within 2 years.[2]

International

Patterns of male infertility vary greatly among regions and even within regions. The highest reported fertility rates are in Finland, while Great Britain has a low fertility rate. A combination of social habits, environmental conditions, and genetics is suspected to contribute to this variation.

Debate has occurred in the literature regarding a poorer semen quality, decreased sperm counts (113 million/mL in 1940 compared with 66 million/mL in the 1990s), and decreased fertility in men today compared with fertility 50 years ago.[3] Investigators hypothesize that environmental conditions and toxins have led to this decline; however, others argue that this is solely because of differences in counting methods, laboratory techniques, and geographic variation.

Mortality/Morbidity

Many patients who present with infertility as their primary complaint have a serious underlying medical disease, such as pituitary adenomas, hormonally active tumors, testicular cancer, liver and renal failure, and cystic fibrosis (CF). Evaluating patients for such life-threatening or life-altering conditions during the workup is important.

In addition, the risk of cancer appears to be increased in infertile men. In a study of 2238 infertile men, 451 with azoospermia and 1787 without, male infertility was associated with an increased risk of developing cancer in comparison with the general population.[4, 5] Median age at initial evaluation was 35.7 years, and median follow-up was 6.7 years.

Overall, 29 men developed some type of cancer, including 10 (2.2%) with azoospermia and 19 (1.1%) without azoospermia.[5] Compared with the general population of Texas, infertile men had a higher risk of overall cancer (standardized incidence ratio [SIR], 1.7; 95% confidence interval [CI], 1.2-2.5).

The risk was significantly higher in azoospermic men than in nonazoospermic men (SIR, 2.9; 95% CI, 1.4-5.4).[5] The risk of cancer in nonazoospermic infertile men was similar to that in the general population (SIR, 1.4; 95% CI, 0.9-2.2), although there was a trend toward an elevated risk.

The men who developed cancer in the study developed a variety of malignancies, including prostate cancer, testicular cancer, CNS cancer, melanoma, and stomach cancer.[5]

Sex

Isolated conditions of the female are responsible for infertility in 35% of cases, isolated conditions of the male in 30%, conditions of both the male and female in 20%, and unexplained causes in 15%. Even if one partner has an obvious cause for the infertility, a thorough evaluation of both partners for completeness is prudent. In addition, both partners may be aided by evaluation of their sexual practices.

Age

The effect of aging on fertility is unclear. As men age, their testosterone levels decrease, while estradiol and estrone levels increase. Studies have shown that, as men age, their sperm density decreases. Young men have spermatids present in 90% of seminiferous tubules, which decreases to 50% by age 50-70 years and to 10% by age 80 years. Additionally, 50% of Sertoli cells are lost by age 50 years, and 50% of Leydig cells are lost by age 60 years. Despite this, aging men may achieve fertility rates similar to those in younger men, although conception often takes longer.

History

The initial step in the evaluation of an infertile male is to obtain a thorough medical and urologic history. Important considerations include the duration of infertility, previous fertility in the patient and the partner, and prior evaluations. The couple should be asked specifically about their sexual habits, including their level of knowledge of the optimal timing of intercourse and the use of potentially spermatotoxic drugs and lubricants.

Patients should be asked about a history of childhood illnesses such as testicular torsion, postpubertal mumps, developmental delay, and precocious puberty, as well as urinary tract infections, sexually transmitted diseases, and bladder neck surgery. A history of neurological diseases, diabetes, and pulmonary infections should be elicited. Anosmia (lack of smell), galactorrhea, visual-field defects, and sudden loss of libido could be signs of a pituitary tumor. The status of the partner's workup should also be known.

Timing of puberty (early, normal, or delayed)

Precocious puberty, defined as the onset of puberty before age 9 years in males, may be the sign of a serious underlying endocrinologic disorder. Hormonally active tumors from the testicle, adrenal gland, or pituitary, along with adrenal hyperplasia, may result in early puberty.

In contrast, a delay in puberty may be caused by problems with testosterone secretion due to hypothalamic, pituitary, or testicular insufficiency or to end-organ androgen insensitivity.

Childhood urological disorders or surgery

Consider the following:

Prenatal exposure to diethylstilbestrol (DES) may cause epididymal cysts and cryptorchidism.

Prior bladder neck procedure, such as a V-Y plasty performed at the time of ureteral reimplantation, may lead to retrograde ejaculation.

The vas deferens or the testicular blood supply may be injured or ligated at the time of inguinal surgery, hernia repair, hydrocelectomy, or varicocelectomy.

Testicular torsion and trauma may result in testicular atrophy and the production of antisperm antibodies.

Medical history

In males, decreased general health status appears to be associated with impaired reproductive health.[6] Effects of specific disorders on fertility include the following[7] :

Acute and chronic medical illnesses

Patients should be asked about recent acute febrile illnesses, which may temporarily suppress gonadotropin release. The decrease in sperm production may not be realized until 1-3 months later.

Anesthesia, surgery, starvation, myocardial infarction, hepatic coma, head injury, stroke, respiratory failure, congestive heart failure, sepsis, and burns are associated with a suppression of gonadotropin release, possibly through an increase in dopamine and opiate levels.

Chronic medical illnesses may directly suppress sex hormone production and sperm production, leading to end-organ failure.

Sexual history

The frequency, timing, and methods of coitus and knowledge of the ovulatory cycle should be elicited. Studies show that the optimal timing for intercourse is every 48 hours at mid cycle.

Lubricants such as Surgilube, Keri lotion, KY Jelly, and saliva are spermatotoxic. Peanut oil, vegetable oil, and petroleum jelly are not known to be spermatotoxic but still should be used in only the smallest amounts possible if needed for lubrication during intercourse.

Testicular cancer

Testicular cancer is associated with impaired spermatogenic function, even before orchiectomy, with a degree of dysfunction higher than that explained by local tumor effect.

Pre-orchiectomy azoospermia has been reported in 5-8% of patients with testicular cancer.[11] Likewise, hormone levels have been found to be abnormal, though specifics may vary depending on the subtype of testicular cancer.

Germ cell tumors may share common etiological factors with testicular dysfunction, such as testicular dysgenesis, androgen insensitivity, and cryptorchidism. Contralateral abnormalities of spermatogenesis are more common in patients with testicular cancer. Sperm function often remains impaired, even after orchiectomy.

Effects of cancer treatment on fertility

Chemotherapy has a dose-dependent effect on germ cells. Alkylating agents, such as cyclophosphamide, mustine, and chlorambucil, severely alter the seminiferous tubules and destroy spermatogonia. (Note that chemotherapy is also mutagenic, so sperm should be donated before treatment, or attempts at conception should be postponed until >1 year after treatment.)

Retroperitoneal lymph node dissection (RPLND) may impair emission (of semen into the urethra) and/or cause retrograde ejaculation.[12]

Radiation therapy affects mainly type B spermatogonia and, possibly, spermatocytes. A dose of as little as 0.15 Gy may cause irreversible damage, although complete recovery may be possible if stem cell numbers are not depleted. After exposure of less than 1 Gy, sperm production may return in 9-18 months, while 4-6 years may be necessary to recover sperm production after a dose of up to 5 Gy. Despite radiation therapy and chemotherapy, nearly two thirds of patients retain the ability to father a child if the ejaculatory function is retained.

To potentially decrease the morbidity of adjunct therapy, select patients with grade I germ cell tumors are now undergoing unilateral orchiectomy with surveillance. However, RPLND performed for salvage therapy is associated with a higher risk of retrograde ejaculation than that performed initially.

Patients with reference range FSH levels at baseline usually observe an improvement in semen parameters and sperm density after orchiectomy. This is thought to be unrelated to the orchiectomy, stress factors, and release of substances by the tumor because decreased sperm counts are observed even before surgery and they do not return to baseline after surgery. Therefore, the disturbance that leads to testicular cancer is thought to be inherent and present in the primordial cell.

Patients with a testicular tumor in a solitary testicle may be offered a partial orchiectomy in an attempt to retain fertility. Additionally, healthy testicular tissue away from the tumor can be dissected free and cryopreserved at the time of orchiectomy for future use in in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI).

Social history

Cigarette and marijuana smoking lead to a decrease in sperm density, motility, and morphology.[13] Abuse of anabolic steroids has been associated with hypogonadism as well as structural and genetic sperm damage.[14]

Alcohol produces both an acute and a chronic decrease in testosterone secretion.

Emotional stress blunts GnRH release, leading to hypogonadism.

Excessive heat exposure from saunas, hot tubs, or the work environment may cause a temporary decrease in sperm production.

Contrary to widely held beliefs, no evidence supports the belief that wearing constrictive underwear, or "briefs," decreases fertility. Even with an elevation in temperature of 0.8-1° caused by wearing constrictive underwear, no changes in sperm parameters, no decrease in spermatogenesis, and no changes in sperm function are observed.[15]

Medicines

Drugs that may impair male fertility include the following:

Family history

Congenital midline defects, cryptorchidism, hypogonadotropism, and testicular atrophy in family members may be a sign of a congenital disease. A history of cystic fibrosis (CF) or hypogonadism should be elicited.

Respiratory disease

Infertility and recurrent respiratory infections may be due to immotile cilia syndrome, which may be isolated or part of Kartagener syndrome (with situs inversus).

CF is associated with congenital bilateral absence of the vas deferens (CBAVD), leading to obstructive azoospermia. While both copies of this recessive gene are necessary for clinical disease, the presence of only one copy may lead to CBAVD.

Young syndrome results in recurrent pulmonary infections and azoospermia due to obstruction of the epididymis by inspissated material.

Environmental and/or occupational exposure

Consider the following:

Spinal cord injury

Severe spinal cord injury (SCI) may lead to anejaculation. These men may be treated with electroejaculation or sperm retrieval techniques.[17]

In addition, the semen quality in patients with SCI may gradually decline. Within a year after injury, many of these patients have semen with dead sperm, with signs of neutrophil infiltration on semen analysis.

In patients with SCI, sperm aspirated from the vas deferens show 54% motility and 74% viability, while only 14% motility and 26% viability is observed in ejaculated sperm, which suggests an abnormality of seminal plasma.[18] Studies of seminal plasma point to functional failure of the prostate gland, likely from lack of neurogenic stimulation, along with hyperactivation of the immune system, which is probably not triggered by microbial infection, as causal elements for infertility related to SCI.[19]

Additionally, infertile men with SCI has been shown to have disruptions in nuclear maturity and DNA integrety of spermatozoa and as a consequence may have higher rates of apoptosis, which possibly contributes to infertility.[20]

 

Physical

The physical examination should include a thorough inspection of the testicles, penis, secondary sexual characteristics, and body habitus. It should include a detailed examination of other body functions based on the history.

Testicles

The testicular examination should occur in a warm room with the patient relaxed. The testicles should be palpated individually between the thumb and first 2 fingers. The examiner should note the presence, size, and consistency of the testicles, and the testicles should be compared with each other.

A Prader orchidometer or ultrasonography may be used to estimate the testicular volume, with normal considered to be greater than 20 mL.

Calipers may be used to measure testicular length, which is usually greater than 4 cm, although the lower limits of normal length (mean minus 2 standard deviations) is 31 mm in white men and 34 mm in black men. The testes of Japanese men are typically smaller than the testes of white men.[21]

Testicular atrophy may be observed in patients with any of the following:

Swelling with pain indicates orchitis, whereas nontender enlargement may be observed in testicular neoplasms, tuberculosis, and tertiary syphilis.

Epididymis

The head, body, and tail of the epididymis should be palpated and assessed for their presence bilaterally.

Note induration and cystic changes. An enlarged indurated epididymis with a cystic component should alert the examiner to the possibility of ductal obstruction.

Tenderness may be due to epididymitis.

Vas deferens

Evaluate the vas for its presence bilaterally and palpate along its entire length to check for defects, segmental dysplasia, induration, nodularity, or swelling.

The complete absence bilaterally is observed almost exclusively in patients with either one or two copies of the gene for CF, although even a small defect or gap indicates the possibility of a CF gene mutation.

A thickened, nodular vas deferens may be observed in patients with a history of tuberculosis.

If a prior vasectomy has been performed, the presence of a nodular sperm granuloma at the proximal vasal end should be assessed.

Spermatic cord

Check patients for the presence of a varicocele, which is the most common surgically correctable cause of infertility (see image below). To elicit this, the patient should perform a Valsalva maneuver in the sitting and standing positions in a warm room. Grade 1 varicocele is defined as palpable only with Valsalva, while grade 2 is palpable at standing, and grade 3 is visible at rest. The presence of asymmetry or an impulse with Valsalva may best help the examiner find a varicocele.



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Male infertility. Varicocele. A - Physical examination revealing the characteristic "bag of worms." B - Anatomy of the dilated pampiniform plexus of v....

The sudden onset of a varicocele, a solitary right-sided varicocele, or a varicocele that does not change with Valsalva indicates the possibility of a retroperitoneal neoplastic process or vein thrombosis.

Penis

The examination should focus on the location and patency of the urethral meatus and the presence of meatal strictures.

Patients with hypospadias or epispadias may not deposit semen appropriately at the cervix.

Penile curvature and the presence of penile plaques should be noted.

Rectal examination

The prostate should be of normal size and without cysts, induration, or masses.

The seminal vesicles are usually not palpable.

A midline prostatic cyst or palpable seminal vesicles may be due to obstruction of the ejaculatory ducts.

Body habitus

A eunuchoid body habitus, consisting of infantile hair distribution, poor muscle development, and a long lower body due to a delayed closure of the epiphyseal plates, may be observed in patients with endocrinological disorders.

Truncal obesity, striae, and moon facies may be due to Cushing syndrome.

Gynecomastia, galactorrhea, headaches, and a loss of visual fields may be observed in patients with pituitary adenomas.

Focus the neck examination on thyromegaly and bruits.

Palpate the liver for hepatomegaly and examine the lymph nodes to rule out lymphoma.

Causes

Causes generally can be divided into pretesticular, testicular, and post-testicular.

Pretesticular causes of infertility

Pretesticular causes of infertility include congenital or acquired diseases of the hypothalamus, pituitary, or peripheral organs that alter the hypothalamic-pituitary axis.

Disorders of the hypothalamus lead to hypogonadotropic hypogonadism. If gonadotropin-releasing hormone (GnRH) is not secreted, the pituitary does not release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Ideally, such patients respond to replacement with exogenous GnRH or human chorionic gonadotropin (hCG), an LH analogue, although this does not always occur.

Idiopathic hypogonadotropic hypogonadism

A failure of GnRH secretion without any discernible underlying cause may be observed alone (isolated) or as part of Kallmann syndrome, which is associated with midline defects such as anosmia, cleft lip and cleft palate, deafness, cryptorchidism, and color blindness. Kallmann syndrome has been described in both familial (X-linked and autosomal) and sporadic forms, and its incidence is estimated as 1 case per 30,000 male births and 1 per 120,000 female births.

A failure of GnRH neurons to migrate to the proper location in the hypothalamus has been implicated. Patients generally have long arms and legs due to a delayed closure of the epiphyseal plates, delayed puberty, and atrophic testis. Testosterone therapy may allow patients to achieve normal height but does not improve spermatogenesis. Exogenous testosterone should never be administered in an attempt to boost sperm production because it actually decreases intratesticular testosterone levels owing to feedback inhibition of GnRH release.

Pulsatile GnRH and hCG have been used but result in only 20% of patients achieving complete spermatogenesis.

Adding recombinant human FSH to hCG has been shown to be effective in achieving spermatogenesis in most patients, leading to natural conception in most cases.[22]

Select patients with adult-onset idiopathic hypogonadotropic hypogonadism may respond to clomiphene citrate therapy.[23]

Prader-Willi syndrome

Patients have characteristic obesity, developmental delay, small hands and feet, and hypogonadotropic hypogonadism due to a GnRH deficiency. Prader-Willi syndrome is caused by a disorder of genomic imprinting with deletions of paternally derived chromosome arm 15q11-13.

Laurence-Moon-Biedl syndrome

Patients with this syndrome have retinitis pigmentosa and polydactyly. Infertility is due to hypogonadotropic hypogonadism.

Other conditions

Various other lesions and diseases, such as central nervous system tumors, temporal lobe seizures, and many drugs (eg, dopamine antagonists) may interrupt the hypothalamic-pituitary axis at the hypothalamus.

Both pituitary insufficiency and pituitary excess cause infertility. Pituitary failure may be congenital or acquired. Acquired causes include tumor, infarction, radiation, infection, or granulomatous disease. Nonfunctional pituitary tumors may compress the pituitary stalk or the gonadotropic cells, interrupting the proper chain of signals leading to pituitary failure. In contrast, functional pituitary tumors may lead to unregulated gonadotropin release or prolactin excess, interrupting the proper signaling.

Prolactinoma

A prolactin-secreting adenoma is the most common functional pituitary tumor. Prolactin stimulates breast development and lactation; therefore, patients with infertility due to a prolactinoma may have gynecomastia and galactorrhea. In addition, loss of peripheral visual fields bilaterally may be due to compression of the optic chiasm by the growing pituitary tumor.

A prolactin level of more than 150 mcg/L suggests a pituitary adenoma, while levels greater than 300 mcg/L are nearly diagnostic. Patients should undergo an MRI or CT scan of the sella turcica for diagnostic purposes to determine whether a microprolactinoma or a macroprolactinoma is present.

Bromocriptine and cabergoline are dopamine agonists used to suppress prolactin levels. These are both first-line treatment options for microprolactinoma. Some men respond with an increase in testosterone levels; many also recover normal sperm counts. Transsphenoidal resection of a microprolactinoma is 80-90% successful, but as many as 17% recur. Surgical therapy of a macroprolactinoma is rarely curative, although this should be considered in patients with visual-field defects, in cases in which dopamine agonists are unsuccessful at decreasing prolactin levels or tumor size, or in patients who do not tolerate bromocriptine.

Isolated LH deficiency (fertile eunuch)

In these patients, LH levels are decreased while FSH levels are within the reference range. Patients have eunuchoidal body habitus, large testis, and a low ejaculatory volume. The treatment of choice is exogenous hCG.

Isolated FSH deficiency

This is a very rare cause of infertility. Patients present with oligospermia but have LH levels within the reference range. Treatment is with human menopausal gonadotropin (HMG) or exogenous FSH.

Thalassemia

Patients with thalassemia have ineffective erythropoiesis and require multiple blood transfusions. Excess iron from multiple transfusions may be deposited in the pituitary gland and the testis, causing parenchymal damage and both pituitary and testicular insufficiency. Treatment is with exogenous gonadotropins and iron-chelating therapy.

Cushing disease

Increased cortisol levels cause a negative feedback on the hypothalamus, decreasing GnRH release.

Other disorders 

The hypothalamus-pituitary axis may be interrupted by hormonally active peripheral tumors or other exogenous factors, due to cortical excess, cortical deficiency, or estrogen excess.

Excess cortisol may be produced by adrenal hyperplasia, adenomas, carcinoma, or lung tumors. High cortisol levels may also be seen with exogenous steroid use, such as that administered to patients with ulcerative colitis, asthma, arthritis, or organ transplant. For example, high cortisol levels are seen in patients with Cushing syndrome, which causes negative feedback on the pituitary to decrease LH release.

Cortical deficiency may be seen in patients with adrenal failure due to infection, infarction, or congenital adrenal hyperplasia (CAH). CAH may involve deficiency of one of several adrenal enzymes, most commonly 21-hydroxylase. Because cortisol is not secreted, a lack of feedback inhibition on the pituitary gland occurs, leading to adrenocorticotropic hormone (ACTH) hypersecretion. This leads to increased androgen secretion from the adrenal gland, causing feedback inhibition of GnRH release from the hypothalamus. Patients present with short stature, precocious puberty, small testis, and occasionally bilateral testicular rests. Screening tests include assays for increased plasma 17-hydroxylase and urine 17-ketosteroids.

Estrogen excess may be seen in patients with Sertoli cell tumors, Leydig tumors, liver failure, or severe obesity. Estrogen causes negative feedback on the pituitary gland, inhibiting LH and FSH release.

Primary testicular causes of infertility

Primary testicular problems may be chromosomal or nonchromosomal in nature. While chromosomal failure is usually caused by abnormalities of the sex chromosomes, autosomal disorders are also observed.

Chromosomal abnormalities

An estimated 6-13% of infertile men have chromosomal abnormalities (compared with 0.6% of the general population). Patients with azoospermia or severe oligospermia are more likely to have a chromosomal abnormality (10-15%) than infertile men with sperm density within the reference range (1%). A karyotype test and a Y chromosome test for microdeletions are indicated in patients with nonobstructive azoospermia or severe oligospermia (< 5 million sperm/mL), although indications are expanding.[24, 25, 26]

Klinefelter syndrome

Klinefelter syndrome is the most common chromosomal cause of male infertility, estimated to be present in 1 per 500-1000 male births. Classic Klinefelter syndrome has a 47, XXY karyotype and is caused by a nondisjunction during the first meiotic division, more commonly of maternal origin; mosaic forms are due to nondisjunction following fertilization. The only known risk factor for Klinefelter syndrome is advanced maternal age.

Infertility is caused by primary testicular failure, and most patients are azoospermic. Hormonal analysis reveals increased gonadotropin levels, while 60% have decreased testosterone levels. Surprisingly, most patients have normal libido, erections, and orgasms, so testosterone therapy has only a limited role; exogenous testosterone may also suppress any underlying sperm production.

Physical examination reveals gynecomastia, small testis, and eunuchoid body habitus due to delayed puberty.  Other genital abnormalities such as hypospadias, undescended testicles (cryptorchidism) or an unusually small penis (micropenis) can also sometimes be seen. In some patients, secondary sex characteristics develop normally, but they are usually completed late. These men are at a higher risk for breast cancer, leukemia, diabetes, empty sella syndrome, and pituitary tumors. Testicular histology reveals hyalinization of seminiferous tubules.[27]

Some men with Klinefelter syndrome may be able to conceive with the help of assisted reproductive techniques. Of azoospermic patients with Klinefelter syndrome, 20% show the presence of residual foci of spermatogenesis. Although the XXY pattern is observed in the spermatogonia and primary spermatocytes, many of the secondary spermatocytes and spermatids have normal patterns. The chromosomal pattern of the resultant embryos can be assessed with preimplantation genetic diagnosis.

Regular medical follow up is required for patients with Klinefelter syndrome and androgen placement therapy initiation is recommended when testosterone levels are in the hypogonadotropic range after fertility issues have been addressed.[28, 29]

XX male (sex reversal syndrome)

An XX karyotype is due to a crossover of the sex-determining region (SRY) of the Y chromosome (with the testis determining factor) to either the X chromosome or an autosome. Patients are often short, with small firm testis and gynecomastia, but they have a normal-sized penis. Seminiferous tubules show sclerosis.

XYY male

An XYY karyotype is observed in 0.1-0.4% of newborn males. These patients are often tall and severely oligospermic or azoospermic. This pattern has been linked with aggressive behavior. Biopsy reveals maturation arrest or germ cell aplasia. Functional sperm that are present may have a normal karyotype.

Noonan syndrome (46, XY)

Patients with Noonan syndrome, also known as male Turner syndrome, have physical characteristics similar to that of women with Turner syndrome (45, X). Features include a webbed neck, short stature, low-set ears, ptosis, shield-like chest, lymphedema of hands and feet, cardiovascular abnormalities, and cubitus valgus. Leydig cell function is impaired, and most patients are infertile due to primary testicular failure.

Mixed gonadal dysgenesis (45, X/46, XY)

Patients usually have ambiguous genitalia, a testis on one side, and a streaked gonad on the other.

Androgen receptor dysfunction

Because the androgen receptor is essential for the process of spermatogenesis, dysfunctions in this receptor can cause infertility. Reifenstein syndrome in males involves partial androgen insensitivity in males and presents as a spectrum of abnormal external genitalia and infertility.[30] Because cells respond inadequately to androgen stimulation, spermatogenesis is impaired. This results in negative feedback stimulation of the hypothalamic-pituitary axis, causing an increased release of gonadotropins and testosterone.

These receptor dysfunctions may be explained by defects in specific chromosomal areas. A specific portion of the androgen receptor gene, exon 1, has been studied in infertile males and a meta-analysis that involved males with idiopathic infertility and fertile controls found that infertility was directly correlated with the length of CAG repeats in this exon.[31]

Y chromosome microdeletion syndrome

The long arm of the Y chromosome (Yq) is considered critical for fertility, especially Yq11.23 (interval 6). Macroscopic deletions of Yq11 are often observed in patients with azoospermia, although many newly identified microdeletions have been implicated as a significant cause of infertility. These microdeletions are not observed on regular karyotype testing; rather, their identification requires polymerase chain reaction (PCR)–based sequence-tagged site mapping or Southern blot analysis. Three regions have been described, called azoospermic factors a, b, and c (AZFa, AZFb, AZFc).[32, 29]

These deletions are observed in 8-12% of azoospermic males and 3-7% of patients with oligospermia.  AZFc deletions represent the most common type of microdeletion (65-70%), followed by Y-deletions of the AZFb and AZFb+c or AZFa+b+c regions (25-30%). AZFa region deletions are rare (5%). According to European Association of Urology (EAU) and the European Academy of  Andrology (EAA) guidelines, AZF deletion screening is indicated for azoospermic and severely oligospermic patients (< 5 million/mL).[33, 29]

For patients with azoospermia or severe oligospermia seeking assisted reproductive techniques, microdeletion screening is particularly important, as when there are complete AZFa and AZFb microdeletions, the likelihood of sperm retrieval is virtually zero. Therefore testicular sperm extraction (TESE) procedures are contraindicated.  Furthermore, genetic counseling is mandatory in patients found to have AZF deletions, as any Y-deletions will be transmitted to male offspring, putting them at risk for spermatogenic failure, Turner syndrome (45, XO), and other phenotypic abnormalities.[33, 34, 35]

Bilateral anorchia (vanishing testes syndrome)

Patients have a normal male karyotype (46, XY) but are born without testes bilaterally. The male phenotype proves that androgen was present in utero. Potential causes are unknown, but the syndrome may be related to infection, vascular disease, or bilateral testicular torsion. Karyotype shows a normal SRY gene. Patients may achieve normal virilization and adult phenotype through the administration of exogenous testosterone, but they are infertile.

Down syndrome

These patients have mild testicular dysfunction with varying degrees of reduction in germ cell number. LH and FSH levels are usually elevated.

Myotonic dystrophy

This is an autosomal dominant defect in the dystrophin gene that causes a delay in muscle relaxation after contraction. Seventy-five percent of patients have testicular atrophy and primary testicular failure due to degeneration of the seminiferous tubules. Leydig cells are normal. Histology reveals severe tubular sclerosis. No effective therapy exists.

Nonchromosomal testicular failure

Testicular failure that is nonchromosomal in origin may be idiopathic or acquired by gonadotoxic drugs, radiation, orchitis, trauma, or torsion.

Varicocele

A varicocele is a dilation of the veins of the pampiniform plexus of the scrotum. Although varicoceles are present in 15% of the male population, a varicocele is considered the most common correctable cause of infertility (30-35%) and the most common cause of secondary (acquired) infertility (75-85%). Varicoceles are observed more commonly on the left side than the right. Patients with isolated right-sided varicoceles should be evaluated for retroperitoneal pathology.

Varicoceles are generally asymptomatic, and most men with varicoceles do not have infertility or testicular atrophy. However, varicoceles may lead to impaired testicular spermatogenesis and steroidogenesis, potentially due to an increased intratesticular temperature, reflux of toxic metabolites, and/or germ cell hypoxia; this appears to be progressive over time.

Additionally, because insulin-like growth factor (IGF) has been shown to have an effect on semen quality, its role in varicocele pathology has been studied.[36] One study showed that IGF levels significantly increased after a varicocelectomy to levels that were no different than fertile controls, suggesting that varicocele-related infertility may involve IGF.[37]

Varicoceles lead to an increased incidence of sperm immaturity, apoptosis, and necrosis with severe disturbances in meiotic segregation compared with fertile men without varicoceles. These parameters generally improve after repair.

Patients with a grade 1-3 varicocele (visible or palpable) associated with infertility should consider having the varicocele repaired. After repair, 40-70% of patients have improved semen parameters, while 40% are able to impregnate their partner without other interventions. Those with a varicocele diagnosable only on scrotal ultrasonography have subclinical varicoceles and will likely not benefit from repair.[38] Adolescents with a varicocele and testicular atrophy or lack of growth should similarly consider repair.

Controversy exists regarding whether to routinely repair an adolescent varicocele not associated with testicular atrophy. According to the EAU guidelines, prophylactic varicolecetomy is currently advised only in cases of documented testicular atrophy or abnormal semen quality, as most patients with a varicocele will have no problem achieving pregnancy later as adults.[39, 29]

In those with azoospermia and a varicocele, sperm may appear after repair in up to one third, but most of these men return to an azoospermic state within a few months. If sperm appears, these men should be offered cryopreservation.

Cryptorchidism

An estimated 3% of full-term males are born with an undescended testicle, but fewer than 1% remain undescended by age 1 year. Undescended testicle may be isolated or may be observed as part of a syndrome such as prune belly syndrome. Patients are at increased risk of infertility, even if the testicle is brought down into the scrotum, as the testicle itself may be inherently abnormal. The farther from its normal anatomic location in the scrotum and the longer the time that the testicle resides out scrotum, the greater the likelihood of infertility. Testicular histology typically reveals a decreased number of Leydig cells and decreased spermatogenesis. Cryptorchidism may be due to inherent defects in both testes because even men with unilateral cryptorchidism have lower than expected sperm counts.

Trauma

Testicular trauma is the second most common acquired cause of infertility. The testes are at risk for both thermal and physical trauma because of their exposed position.

Sertoli-cell-only syndrome (germinal cell aplasia)

Patients with germinal cell aplasia have LH and testosterone levels within the reference range but have an increased FSH level. The etiology is unknown but is probably multifactorial. Patients have with small- to normal-sized testes and azoospermia, but normal secondary sex characteristics. Histology reveals seminiferous tubules lined by Sertoli cells and a normal interstitium, although no germ cells are present.

Chemotherapy

Chemotherapy is toxic to actively dividing cells. In the testicle, germ cells (especially up to the preleptotene stage) are especially at risk. The agents most often associated with infertility are the alkylating agents such as cyclophosphamide. For example, treatment for Hodgkin lymphoma has been estimated to lead to infertility in as many as 80-100% of patients.

Radiation therapy

While Leydig cells are relatively radioresistant because of their low rate of cell division, the Sertoli and germ cells are extremely radiosensitive. If stem cells remain viable after radiation therapy, patients may regain fertility within several years. However, some experts have suggested that patients should avoid conception for 6 months to 2 years after completion of radiation therapy because of the possibility of chromosomal aberrations in their sperm caused by the mutagenic properties of radiation therapy. Even with the testis shielded, radiation therapy below the diaphragm may lead to infertility due to the release of reactive oxygen free radicals.

Orchitis

The most common cause of acquired testicular failure in adults is viral orchitis, such as that caused by the mumps virus, echovirus, or group B arbovirus. Of adults who are infected with mumps, 25% develop orchitis; two thirds of cases are unilateral, and one third are bilateral. While orchitis typically develops a few days after the onset of parotid gland inflammation, it may also precede it.

The virus may either directly damage the seminiferous tubules or indirectly cause ischemic damage as the intense swelling leads to compression against the tough tunica albuginea. After recovery, the testicle may return to normal or may atrophy. Atrophy is observed within 1-6 months, and the degree of atrophy does not correlate with the severity of orchitis or infertility. Normal fertility is observed in three fourths of patients with unilateral mumps orchitis and in one third of patients in bilateral orchitis.

Human-beta defensin abnormalities

Epididymis human-beta defensin is a protein that has been shown to have an important role in sperm maturation, and defects in it have been associated with decreased egg-penetrating ability.[40] One specific subtype, human-beta defensin–1 (HBD1), which has a wide distribution in various epithelia throughout the body and plays a role in antimicrobial activities against viruses, bacteria, and fungi, has also been investigated.

HBD1 is expressed in the seminal plasma and ejaculated sperm, more specifically in the lower head and midpiece of the sperm from fertile individuals. Expression of HBD1 is reduced in individuals with asthenozoospermia and leukocytospermia. In one study, treatment with recombinant HBD1 in asthenozoospermic and leukocytospermic patients who were deficient in HBD1 resulted in improved bactericidal activity and sperm quality, which supports this protein’s role in fertility and its potential role in managing infertility.[41]

Other causes

Causes of testicular failure also include the following:

Despite a thorough workup, nearly 25% of men have no discernible cause for their infertility.

Post-testicular causes of infertility

Post-testicular causes of infertility include problems with sperm transportation through the ductal system, either congenital or acquired. Genital duct obstruction is a potentially curable cause of infertility and is observed in 7% of infertile patients. Additionally, the sperm may be unable to cross the cervical mucus or may have ultrastructural abnormalities.

Congenital blockage of the ductal system

An increased rate of duct obstruction is observed in children of mothers who were exposed to diethylstilbestrol (DES) during pregnancy. Segmental dysplasia is defined as a vas deferens with at least 2 distinct sites of vasal obstruction.

Cystic fibrosis

CF is the most common genetic disorder in whites. Patients with CF nearly uniformly have CBAVD. The cystic fibrosis transmembrane regulator (CFTR) protein plays a role in mesonephric duct development during early fetal life, so these patients may also have urinary tract abnormalities. Patients may be candidates for assisted reproduction techniques after appropriate genetic screening in the partner.[42]

Acquired blockage of the ductal system

Genital ducts may become obstructed secondary to infections, such as chlamydia, gonorrhea, tuberculosis, and smallpox. Young syndrome is a condition that leads to inspissation of material and subsequent blockage of the epididymis. Trauma, previous attempts at sperm aspiration, and inguinal surgery may also result in ductal blockage. Small calculi may block the ejaculatory ducts, or prostatic cysts may extrinsically block the ducts. Scrotal surgery, including vasectomy, hydrocelectomy (5-6%), and spermatocelectomy (up to 17%), may lead to epididymal injury and subsequent obstruction.[43]

Antisperm antibodies

Antisperm antibodies bind to sperm, impair motility, and lead to clumping, impairing movement through the female reproductive tract and interaction with the oocyte.

Defects in cilia

Immotile cilia syndrome may occur as an isolated disorder or as part of Kartagener syndrome with situs inversus. Because of a defect in the dynein arms, spokes, or microtubule doublet, cilia in the respiratory tract and in sperm do not function properly. In addition to sperm immobility, patients experience sinusitis, bronchiectasis, and respiratory infections.

Ejaculatory duct obstruction

Complete and partial ejaculatory duct obstruction has been implicated as a cause of 1-5% of patients with male infertility. Patients may have a normal palpable vas deferens bilaterally but show decreased ejaculate volume and hematospermia and may experience pain upon ejaculation. Etiologies include cysts (midline and eccentric), ductal calcification and stones, postinfectious, and postoperative. Transrectal ultrasonography (TRUS) may reveal enlarged seminal vesicles, but this is not universal. The American Urologic Association (AUA) recommends transrectal ultrasound for patients with palpable vasa and low ejaculate volumes.[25, 44]

Ejaculation issues

Anejaculation/retrograde ejaculation may be due to an open bladder neck or a lack of rhythmic contractions during ejaculation. Etiologies include the following:

The diagnosis of anejaculation or retrograde ejaculation is suggested by the following:

Laboratory Studies

Semen analysis

The semen analysis is the cornerstone of the male infertility workup. A specimen is collected by masturbation into a clean, dry, sterile container or during coitus using special condoms (containing no spermicidal lubricants). The patient should be abstinent for 2-3 days prior to maximize sperm number and quality. Each day of abstinence is typically associated with an increase in semen volume of 0.4 mL and an increase in sperm density by 10-15 million sperm/mL, for up to 7 days.

The sample should be processed within 1 hour, and 2-3 samples (at a minimum of 2-3 days apart) should be evaluated because of daily variations in sperm number and quality. Various parameters are measured, such as ejaculate volume and sperm density, quality, motility, and morphology. Individual tests evaluate only one aspect of a quality necessary for fertility and do not imply the ability or inability to achieve conception (see the Table in the Procedures section).

The World Health Organization (WHO) published reference ranges for semen testing in 2010.[45] These include “lower reference limits” representing the 5th percentiles for semen characteristics.[46] Note that the lower reference limits do not serve as a cut-point between “fertile” and “infertile.”

Volume

Normal ejaculate volume is 1.5-5 mL, and the WHO lower reference limit (5th percentile) is 1.5 mL. A small ejaculate volume may be observed in patients with retrograde ejaculation, absence of the vas deferens or seminal vesicles, ductal obstruction, hypogonadotropism, or poor sympathetic response. An increased volume is rarely observed and is often caused by a contaminant, such as urine.

Semen quality

Semen is initially a coagulum that liquefies in 5-25 minutes due to prostatic enzymes. At this point, pouring the semen drop by drop should be possible. Semen that is not initially a coagulum is often an indication of an ejaculatory duct obstruction or the absence of seminal vesicles. Nonliquefication of the semen can be differentiated from benign hyperviscosity by a normal postcoital test finding. No excessive sperm agglutination should exist.

Sperm density

Normal sperm density is greater than 20 million sperm/mL. The WHO lower reference limit (5th percentile) is 15 million sperm per mL, or 39 million sperm per ejaculate. Oligospermia is defined as fewer than 20 million sperm/mL, severe oligospermia is less than 5 million/mL, and azoospermia is defined as no sperm present.

To verify azoospermia, the semen should be centrifuged and evaluated under a light microscope for the presence of sperm. Patients with azoospermia should have a postejaculatory urine sample analyzed for sperm, should be evaluated for ejaculatory duct obstruction, and should undergo a hormonal evaluation.

Sperm motility

Motility is described as the percent of sperm present with flagellar motion viewed on a bright-field or phase-contrast microscope. Normal motility is defined as more than 60% of sperm having normal movement, and the WHO 2010 lower reference limit (5th percentile) is 40%. Grading is as follows:

Patients with abnormal sperm motility should be evaluated for the following:

Sperm morphology

The head, acrosome, mid piece, and tail of individual spermatozoa are analyzed with phase-contrast microscopy after fixation with Papanicolaou stain. At least 200 sperm are analyzed. Normal sperm have a smooth oval head approximately 3-5 μm long and 2-3 μm wide. More than 60% of sperm should be normal, and less than 2-3% should be immature. These sperm show a high level of retained cytoplasmic droplets around the mid piece.

Teratospermia is defined as less than 30% normal morphology, and the WHO lower reference limit (5th percentile) is 4%. Abnormal head shapes are described as tapered, duplicated, small, large, amorphous, or pyriform. The acrosome should be 40-70% of the size of the head, and no mid piece or tail abnormalities should be present.

Patients with a high number of immature sperm should be evaluated for excessive exposure to heat or radiation or for infectious processes.

To help objectify sperm morphology and therefore enhance the consistency and reproducibility among laboratories, Kruger introduced a definition of "strict criteria" in 1986. Using these criteria, he reported a clinically significant threshold of 14% normal forms as an excellent predictor of IVF success. Patients with less than of 14% normal forms had a substantially reduced success rate.

Computer-aided semen analysis (CASA)

Introduced in the late 1980s, CASA uses a video camera and computer to visualize and analyze sperm concentration and movement. This semiautomated technique is thought to potentially standardize the evaluation of semen. CASA measures the following parameters:

In addition, the program measures the average path velocity, the amplitude of lateral head displacement, and the flagellar beat frequency, and it is used to evaluate for evidence of hyperactivation.

Although CASA produces good qualitative data, it is a labor-intensive procedure with a high initial cost and is plagued with inaccuracies when sperm concentrations are very high or very low. It has not been shown to improve patient outcomes but, rather, is helpful for research purposes.

Infection

An increased number of white blood cells in the semen may be observed in patients with infectious or inflammatory processes of the genital tract. Germ cells and white blood cells both appear as round cells on microscopic examination, so immunohistochemical stains are used to differentiate the 2 cell types. Immunohistochemical stains are performed if more than 5-10 round cells/HPF are present. 

Other tests

Semen may be analyzed for levels of zinc, citric acid, acid phosphatase, and alpha-glucosidase. These tests are used to determine gland failure or obstruction.

Antisperm antibody test

Sperm contain unique antigens that are not recognized as self by the body's immune system because of the blood-testis barrier.

Antisperm antibodies may form when the blood-testis barrier is breached because of infection, vasectomy, testicular torsion, cryptorchidism, or testicular trauma. Antibodies that are bound to sperm decrease the sperm’s ability to penetrate the cervical mucus and bind to the zona pellucida.

Although 60% of patients have evidence of antisperm antibodies after vasectomy, the clinical significance has not been completely elucidated. In addition, antibodies are present in 35% of patients with CBAVD. The presence of antibodies in serum or seminal plasma is less prognostic than antibodies bound to sperm.

Suspect antisperm antibodies when semen analysis reveals abnormal clumping, agglutination, unexplained decreased motility, or an abnormal postcoital test result.

Several methods are available to detect antisperm antibodies, such as radioimmunoassay and enzyme-linked immunosorbent assay, but the most specific test is the immunobead test. More than 15-20% bound is considered a positive test result.

Hormonal analysis

Around 3% of cases of male infertility are estimated to be due primarily to a hormonal cause. A routine part of the initial evaluation is testing of specific serum hormone levels, which usually includes FSH, LH, testosterone, and prolactin. Abnormalities may be a sign of a primary hypothalamic, pituitary, or testicular problem.

Imaging Studies

Transrectal ultrasonography

TRUS is indicated in patients with azoospermia or severe oligospermia to evaluate for complete or partial ejaculatory duct obstruction, particularly when the vasa are palpable and low ejaculate volume is noted.[25, 26]  TRUS is also useful to evaluate for the presence or absence of the seminal vesicles.

A 6.5- to 7.5-MHz probe is used with the bladder partially filled.

Obstruction is suggested by enlarged seminal vesicles (>1.5 cm width).

Scrotal ultrasonography

Scrotal ultrasonography is used to evaluate the anatomy of the testis, epididymis, and spermatic cord. It is a useful adjunct for evaluating testicular volume, testicular and paratesticular masses, and the presence or absence of varicoceles.

A large review reported a 38% rate of abnormalities on testicular ultrasonography in infertile men, including 30% with varicocele and 0.5% with testicular cancer.[47]

Routine testicular ultrasonography in infertile men is controversial, but some suggest it because of the increased risk of testicular cancer in infertile men (1 of 200 versus 1 of 20,000 in the general population).[48]

Color-flow ultrasonography is used to evaluate for varicocele using a 7- to 10-MHz probe.

A varicocele is diagnosed on a sonogram if a spermatic vein is greater than 3 mm or vein size increases with Valsalva. Repair of subclinical varicoceles (those diagnosed only with ultrasonography) has not been proven to improve fertility.[38]

Vasography

Vasography is used to evaluate patency of the ductal system.

Indications for vasography include azoospermia with sufficient mature spermatids present on testicular biopsy and at least one palpable vas.

Relative indications include severe oligospermia with a normal finding on testis biopsy, antisperm antibodies, and decreased semen viscosity.

This test may be performed either as an open procedure at the same time as testicular biopsy or by a percutaneous puncture (see image below).



View Image

Male infertility. Technique of open vasography: The vas distal to the site of incision is determined to be patent if saline is injected without resist....

The patient may be placed in a 10-15° Trendelenburg position to bring the symphysis pubis out of the radiation field.

Unilateral patency rules out vasal or ejaculatory duct obstruction as the cause of azoospermia.

Other Tests

Postcoital test

An abnormal postcoital test result is observed in 10% of infertile couples. Indications for performing a postcoital test include semen hyperviscosity, increased or decreased semen volume with good sperm density, or unexplained infertility.

After coitus at mid cycle, the female's cervical mucus is examined for the presence or absence of sperm. Usually, 10-20 sperm/HPF are observed. Abnormal results may be due to antisperm antibodies, sperm ultrastructural abnormalities, an abnormal hormonal milieu, male or female genital tract infection, poor semen quality, inhospitable cervical mucus, or male sexual dysfunction. If no sperm are observed, the couple's coital technique should be analyzed.

If the test result is normal, consider a test of sperm function and ability to penetrate the egg.

Sperm function tests

When a primary sperm defect is suspected or when other tests do not reveal the cause of infertility, sperm function tests may determine if a significant sperm abnormality exists. These tests analyze specific sperm functions, such as the ability to undergo capacitation and the acrosome reaction and the ability to bind to and to penetrate the egg.

The capacitation assay is used to evaluate the ability of sperm to undergo capacitation. After capacitation, sperm have hyperactivated motility, which can be recognized under microscopy. Failure of sperm to undergo capacitation portends a poor response to IVF, and ICSI should be considered.

The acrosome reaction assay tests the ability of the sperm to undergo the acrosome reaction when exposed to inducing substances. The acrosome process, which covers the anterior two thirds of the sperm head, contains hyaluronidase and other enzymes used to digest the zona pellucida of the egg. After sperm binding and capacitation, the plasma membrane of the egg induces the acrosome to release its contents. This reaction occasionally occurs spontaneously (< 10% of the time), although a spontaneous reaction is more common in infertile men.

Under the microscope, acrosome-inducing substances are added to the sample after the sperm have undergone capacitation, which usually takes approximately 3 hours. Usually, 15-40% of the sperm undergo the acrosome reaction when stimulated, and fewer undergo the reaction in infertile men. The results of the test correlate with IVF success; patients with an abnormal test result may need to undergo ICSI.

Sperm penetration assay (SPA)

First described in 1976 by Yanagimachi et al, the SPA is used to check the ability of sperm to function in vitro by evaluating capacitation, the acrosome reaction, and the ability of the sperm to fuse with the oolemma.[49]  Because cross-species fertilization is usually prevented by the zona pellucida, the SPA uses hamster ova with the zona pellucida removed. These ova are incubated with the donor's sperm and the number of sperm penetrated per ovum is measured. A normal result is more than 5 sperm penetrations per ovum. Fewer penetrations probably indicate a problem. Patients with a poor SPA should proceed directly to ICSI.

Hypoosmotic swelling (HOS)

The HOS test is used to provide functional information to differentiate between viable but immotile sperm and dead sperm. Normal sperm are able to maintain an osmotic gradient when exposed to hypoosmotic conditions, whereas dead sperm cannot. After exposure to a dilute solution (150 mmol/L), sperm are observed under the microscope. Normal sperm swell, with bulging of the plasma membrane and curling of the tail. This test is commonly used clinically to select viable (but nonmotile) sperm for ICSI.

Inhibin B

Inhibin B is usually produced by sperm for the acrosome reaction. An increased level or an inability to clear acrosomal enzymes may lead to self-destruction and lipid peroxidation of the sperm membrane. Increased inhibin B levels may be caused by ductal obstruction or abnormalities within the seminiferous tubules.

Vitality stains

Vitality stains using substances such as eosin Y and trypan blue help determine whether sperm are alive and their membrane is intact or if the sperm are dead. Live sperm can exclude dye, while dead sperm cannot. These tests are of little use unless very low numbers of sperm exist or motility is absent and necrospermia must be ruled out. The subsequent process of slide fixation kills all of the sperm, thus preventing their clinical use.

Procedures

Testicular biopsy

Testicular biopsy is performed in azoospermic men with a normal-sized testis and normal findings on hormonal studies, for the following indications:

The procedure may be performed under spinal, general, or even local anesthesia, and it may be performed as an open procedure or percutaneously. Open surgery allows better testicular control and generally results in a better test, allowing multiple areas to be sampled for the presence or absence of sperm. A touch preparation of the testicular tissue, obtained from either an open or needle-core biopsy, may aid in a prompt evaluation during the procedure and, if used on a sterile slide, may even be cryopreserved for later use.

An operating microscope is often helpful to assist in identification of healthy-appearing tubules, especially in patients with Sertoli-cell–only syndrome.

In addition, vasography may be performed at the same time to evaluate for obstruction.

Potential complications include pain, bleeding, and inadvertent epididymal biopsy that may give false results and can lead to secondary obstruction.

A small window should be used if a later reconstruction is anticipated, to decrease the risk of adhesions within the tunica vaginalis.

Hemostasis must be pristine to decrease the risk of a hematocele.

When performing diagnostic biopsies, consider obtaining biopsies from both testicles, due to a reported 40% discordance in pathology between the 2 sides.

Usually, it is recommended that testicular tissue be cryopreserved at the time of biopsy for potential future use in IVF.

Table. Abnormal Findings on Semen Analysis: Possible Follow-up Tests*



View Table

See Table

Histologic Findings

Biopsy samples in patients with infertility from pretesticular causes have atrophic cells due to a lack of gonadotropin stimuli. Prepubertal hypogonadotropism leads to small, immature seminiferous tubules with delicate tunica propria and a lack of elastic fibers. In contrast, patients with postpubertal hypogonadism show few or no germ cells, shrunken tubules, and a thickened, hyalinized tunica propria.

Primary testicular failure causes various defects. Normal-sized seminiferous tubules, normal Leydig cells and Sertoli cells, and a normal tunica propria characterize maturation arrest, but germ cells are arrested at any premature stage. Patients with hypospermatogenesis have a thin germinal epithelium and a decreased number of germinal elements. Germ cell aplasia (Sertoli-cell–only syndrome) is associated with vacuolated Sertoli cells and no germinal epithelium but otherwise normal seminiferous tubules. Klinefelter syndrome is characterized by a decreased number of spermatogonia, germ cell hypoplasia, Sertoli cell atrophy, tubular hyalinization, prominent Leydig cells (hyperplasia), and deformed tubules. Cryptorchid testes have small immature tubules, spermatogonia of variable size, and a hyalinized tunica propria.

Acute mumps orchitis is associated with interstitial edema, mononuclear infiltrate, and a degeneration of germinal epithelium, while recovery is characterized by a patchy loss of germ cells with tubular hyalinization and sclerosis.

Posttesticular obstruction leads to increased tubule diameter, increased thickness of the tunica propria, and a decreased number of Sertoli cells and spermatids. Sloughing of the germinal epithelium may be present.

Medical Care

A limited number of medical treatments are available for improving chances of conception in men with certain causes of infertility.

Endocrinopathies

A number of patients with hypogonadotropic hypogonadism respond to gonadotropin-releasing hormone (GnRH) therapy or gonadotropin replacement. Pulsatile GnRH therapy can be used in those with intact pituitary function. Gonadotropin replacement can be effective in hypothalamic and pituitary dysfunction.

Human chorionic gonadotropin (hCG) is a luteinizing hormone (LH) analogue that may be used alone or in combination with human menopausal gonadotropin (hMG) for Leydig cell stimulation. hCG is biologically similar to LH, but has a longer half life and is less costly than LH. hMG is a purified combination of follicle-stimulating hormone (FSH) and LH. When using hCG in combination with hMG or FSH, one should use hCG first, as it increases testosterone levels, which is essential for spermatogenesis and thus may better augment the overall effect of the therapy.[50] FSH alone is not effective in inducing spermatogenesis, although recent studies suggest otherwise.[51]

Estrogen modulators can also be of use. Aromatase inhibitors (eg, anastrozole) block the conversion of testosterone to estrogen, thus increasing the serum testosterone concentration.They are especially useful in improving semen parameters in patients with decreased testosterone:estradiol ratios.[52]

Clomiphene citrate is a weak estrogen-receptor antagonist that works by blocking the negative feedback inhibition of estrogen on the anterior pituitary, thus increasing the release of FSH and LH. This will then result in increased testosterone production, ultimately augmenting spermatogenesis. Clomiphene citrate is effective in improving the semen parameters in patients with hypogonadotropic hypogonadism.[53] Tamoxifen is another estrogen-receptor antagonist that, in combination with clomiphene, can increase sperm concentration, sperm motility, and pregnancy rates in males with idiopathic infertility.[54]

Patients with congenital adrenal hyperplasia (CAH) may respond to therapy with glucocorticoids, while those with isolated testosterone deficiency may respond to testosterone replacement.

Exogenous testosterone decreases intratesticular testosterone production, thus inhibiting Sertoli cell function and spermatogenesis. Consequently, it is not recommended for use in treatment of infertile males who desire parenthood.

Treatment of hyperprolactinemia is with dopamine antagonists, such as bromocriptine or cabergoline. In certain patients with prolactinomas, transsphenoidal surgery is indicated, but generally medically management is advocated first.

Antisperm antibodies

Use of steroids in patients with steroids is controversial, with some studies showing improvement in spermatozoal quality and conception rates and others showing no benefit in rates of conception.[55, 56] Patients with antisperm antibody levels greater than 1:32 may respond to immunosuppression using low-dose steroids for 3-6 months. However, patients need to be aware of the potential adverse effects of steroids, including avascular necrosis of the hip, weight gain, and iatrogenic Cushing syndrome.

Retrograde ejaculation

Imipramine or alpha-sympathomimetics, such as pseudoephedrine, may help close the bladder neck to assist in antegrade ejaculation. However, these medicines are of limited efficacy, especially in patients with a fixed abnormality such as a bladder neck abnormality occurring after a surgical procedure.

Alternatively, sperm may be recovered from voided or catheterized postejaculatory urine to be used in assisted reproductive techniques. The urine should be alkalinized with a solution of sodium bicarbonate for optimal recovery.

More recently, the injection of collagen to the bladder neck has allowed antegrade ejaculation in a patient who had previously undergone a V-Y plasty of the bladder neck and for whom pseudoephedrine and intrauterine insemination had failed.[57]

Semen processing

Patients with poor semen quality or numbers may benefit from having their semen washed and concentrated in preparation for intrauterine insemination.

Couples with an abnormal postcoital test result due to semen hyperviscosity may benefit from a precoital saline douche or semen processing with chymotrypsin.

Lifestyle

Patients should be encouraged to stop smoking cigarettes and marijuana and to limit environmental exposures to harmful substances and/or conditions.

Stress-relief therapy and consultation of other appropriate psychological and social professionals may be advised.

Infections should be treated with appropriate antimicrobial therapy.

Dietary supplements and vitamins

Safarinejad et al published a prospective, double-blind, randomized controlled trial assessing the effects of coenzyme Q10 (ubiquinol) 200 mg po daily (n = 114 men) compared with placebo (n = 114 men) over 26 weeks. The authors found a statistically significant increase in sperm concentration, motility, and strict morphology in subjects who received ubiquinol compared with those who received placebo, and these effects gradually returned to baseline levels during the off-drug time period. While pregnancy rates were not tracked or reported, the improvement in semen parameters does appear to support the use of ubiquinol in men trying to achieve a pregnancy.[58]

Surgical Care

Varicocelectomy

Various techniques for varicocelectomy have been proposed and used, including retroperitoneal, inguinal, and subinguinal approaches. Each has advantages and disadvantages.

The retroperitoneal approach may be performed as an open procedure or laparoscopically.

The inguinal approach (see image below) allows for ligation of individual veins with decreased risk of inadvertent arterial damage. A 3-5 cm incision is made over the inguinal canal and the spermatic cord is identified and elevated. The external veins parallel to the cord are ligated, followed by microscopic ligation of the spermatic veins Collateral vessels entering the cord distally may also be directly addressed with this technique. This is in contrast to the subinguinal approach, in which a greater number of arteries and veins are exposed and the dissection may be more difficult.[59]



View Image

Male infertility. Technique of microscopic varicocelectomy. The individual veins of the pampiniform plexus are isolated (top) and ligated, taking care....

Successful varicocelectomy results in improvement in semen parameters in 60-70% of patients. The repair also typically halts further testicular damage and improves Leydig cell function. Preoperative factors that predict success with these repairs include the following[60, 61] :

Persistent dilatation after repair is not unusual and does not necessarily represent surgical failure. Rather, the veins may remain clinically apparent owing to chronic stretching or thrombosis, even if venous reflux is no longer present. Semen analysis may show improvement as early as the 3-month follow-up visit.[62]

Results from a prospective, randomized, controlled trial from Saudi Arabia provide an evidence-based endorsement of the superiority of subinguinal microsurgical varicocele repair over observation in infertile men with palpable varicoceles and impaired semen quality.[63] Inclusion criteria included infertility lasting 1 year or longer, demonstration of a palpable varicocele, and presence of at least one impaired semen parameter (sperm concentration < 20 million/mL, progressive motility < 50%, or normal morphology < 30%). A total of 145 participants had follow-up within 1 year; spontaneous pregnancy was achieved in 32.9% of treated men compared with 13.9% of controls (odds ratio, 3.04). In treated men, the mean of all semen parameters significantly improved on follow-up compared with baseline (P < 0.0001).

A meta-analysis that compared the various varicocelectomy approaches found that pregnancy rates increased in inguinal, subinguinal, open inguinal, and laparoscopic approaches. However, the subinguinal and inguinal groups had the lowest recurrence rates, highest pregnancy rates, greatest increases in sperm parameters, and lowest rate of hydrocele formation.[64]  

Interest in the use of robotic surgery has been growing across various medical fields, including varicocelectomy. The potential advantages of robotic-assisted microsurgery include the following[65, 66] :

Robot-assisted subinguinal varicocelectomy has been shown to be safe and efficacious, with one group reporting improved sperm parameters in 76% of patients.[67] Operative times are similar to those with microscopic inguinal varicocelectomy, although the robotic technique does have a learning curve.[68]

Vasovasostomy or vasoepididymostomy

These microsurgical techniques are performed in patients with known epididymal or vasal obstruction, both congenital and acquired (eg, due to surgery, trauma, infection). Improved surgical techniques and the use of the operating microscope have improved the outcomes in patients requiring vasectomy reversal or those with primary vas obstruction.[69] In a study by Fenig et al, the timing of a reversal along with a sperm granuloma identified during the patient’s physical examination have been identified as predictors of the need for epididymovasostomy.[70]

In addition, men with increased follicle-stimulating hormone levels of >10 U/L may have an increased likelihood of needing assisted reproduction to achieve pregnancy after vasectomy reversal, according to a study by the Goldstein group of Weill Cornell Medical College.[71]

After scrotal exploration, the patency of the duct system proximal to the proposed site of anastomosis is confirmed by examination of expressed fluid for the presence of sperm. If no fluid is expressed, a 24-gauge angiocatheter with 0.1 mL of saline should be used to gently barbotage the proximal vas. If no sperm are observed, inspect the vasal fluid aspirated.

A thickened, white, toothpaste-like fluid usually contains no sperm or nonviable sperm fragments and is likely merely from the vasal epithelium, whereas a watery thin fluid often implies proximal patency.[72] If viable sperm are observed, send an additional sample for cryopreservation prior to vasovasostomy. These sperm may be used for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) if the man remains azoospermic after the repair.

The patency of the distal duct system is confirmed by injecting 10 mL of sterile saline through the vas; if no resistance is encountered, the system is deemed patent. Alternatively, radiographic vasography or chromogenic vasography with methylene blue can be performed, with radiographic contrast visualized passing into the bladder or blue coloration of the urine proving patency, respectively. A 2-0 nylon suture can be passed into the vasal lumen to check the distance to obstruction if the above tests reveal distal blockage.

A vasovasostomy is generally performed in 2 layers, the inner lining with interrupted 10-0 nylon suture and the outer layer with interrupted 9-0 nylon suture (see image below). Optimally, a tension-free, mucosa-to-mucosa, watertight anastomosis is created.



View Image

Male infertility. Technique of vasovasostomy: Upper left is confirmation of sperm from the proximal vas deferens, proving proximal patency. Upper righ....

A vasoepididymostomy is also closed in 2 layers (see image below). Factors that predict a more favorable outcome include the following:



View Image

Male infertility. Technique of vasoepididymostomy. Left upper is confirmation of mature sperm in epididymis. Right upper is the inner layer anastomosi....

For vasoepididymostomy, an end-to-side technique is easier to perform and yields better outcomes than an end-to-end anastomosis. In 1998, a triangulation end-to-side technique for vasoepididymostomy was described, which has since been broadly implemented.[73] The two-stitch longitudinal intussception technique described by Marc Goldstein is also popular with many microsurgeons due to its simplicity and high patency rates.[74, 75, 76] Although more motile sperm are present at the proximal epididymis in patients with ductal obstruction, the technique is easier and more successful if it is performed at the distal end.

A varicocelectomy and vasovasostomy should never be performed at the same time because of a risk of testicular atrophy.

Robotic vasovasostomy has been shown to yield similar patency rates as the microsurgical approach, but no difference in pregnancy rates (~60%). The mean operating times for robotic vasovasostomy and vasoepididymostomy have also been shown to be comparable to the microsurgical approaches.[65]

Robotic assistance also permits microsurgical procedures to be used in areas that are normally difficult to access. For example, in patients who have a vasal obstruction as a result of a prior inguinal hernia repair, robotic-assisted intra-abdominal vasovasostomy has been effectively employed.[68] It provides an advantage to these patients because it requires very small inguinal incisions to mobilize the external vas and it allows for tension-free anastomosis because the testicular vas is brought into the pelvis for the procedure.[67]

Transurethral resection of the ejaculatory ducts

Patients with a known or suspected obstruction of the ejaculatory ducts may be eligible for transurethral resection of the ejaculatory ducts (TURED), which durably improves semen quality in patients with ejaculatory duct obstruction.

In the operating room, with the patient under spinal or general anesthesia, the resectoscope with a 24F cutting loop is used to excise the verumontanum of the prostate. A video example of this has been provided by Savio et al.[77] Using the O'Connor drape to enable placement of a finger in the rectum to elevate the prostate may be helpful.

Resection is performed with care to avoid injuring the bladder neck or external sphincter.

Risks with this procedure include watery (urine-contaminated) ejaculate, chemical or bacterial epididymitis due to reflux, bleeding, and retrograde ejaculation.

Sperm retrieval techniques

Testicular sperm extraction (TESE) is performed at the time of testicular biopsy or as a separate procedure using the same technique.[78] In a study spanning 15 years, TESE from men with azoospermia followed by cryopreservation was more effective at fertilization than fresh sperm from biopsies (62% vs 47% for all diagnoses).[79, 80]

Microscopic TESE (microTESE) has been shown to improve sperm retrieval rates with minimal tissue excision.During microdissection, the surgeon can identify sperm-producing areas in the testicles, which is not possible with standard TESE.[81] Robotic-assisted TESE (ROTESE) has been employed in select studies and has been shown to be safe and feasible for sperm retrieval. An advantage of ROTESE over microTESE is that ROTESE can provide surgeons with multiple imaging modalities to use during the procedure, which may assist in identifying tubules that contain sperm.[65]

Testicular sperm aspiration (TESA) is less invasive than TESE but yields fewer sperm and is suboptimal in cases of nonobstructive azoospermia.[78]

Microsurgical epididymal sperm aspiration (MESA) involves directly retrieving sperm from the epididymis. Sperm in the epididymis are more mature than those in the testis. Using a microscope, the epididymis is uncovered and incised to express sperm. Epididymal fluid is aspirated into a tuberculin syringe primed with human tubal fluid (HTF).

Percutaneous epididymal sperm aspiration (PESA) involves direct sperm aspiration from the epididymis. This procedure can be performed under local anesthesia in the office setting.[82] While effective in sperm retrieval, PESA does not allow sampling from multiple sites and is associated with an increased risk of epididymal and testicular injury and secondary epididymal obstruction.

An autogenous spermatocele can be created in patients with an unreconstructable ductal system. A buttonhole is created within the viscera, and repeated percutaneous aspirations of sperm can be performed using ultrasonographic guidance. An intact tunica vaginalis with no adhesions is needed, so it is ideal for use in patients with normal spermatogenesis and a congenital absence of the vas. This procedure is rarely used.

An alloplastic spermatocele uses an artificial silicone sperm reservoir in place of the tunica vaginalis for sperm storage and subsequent retrieval. This technique has been unsuccessful so far.

Electroejaculation

With the patient under general anesthesia, an unlubricated Foley catheter is placed in the bladder and a buffer (ie, HTF medium) is instilled through the catheter. A rectal probe is inserted with its electrodes positioned against the posterior seminal vesicles. Electrical stimulation is begun at 3-5 volts and increased as necessary. Electroejaculation achieves up to a 90% sperm retrieval rate.

The penile vibratory stimulator has been shown to be a useful alternative to electroejaculation in select patients.[83] Patients must have an intact lumbosacral spinal cord segment. The US Food and Drug Administration (FDA) has approved this device for home use, using 2.2 mm at 100 Hz. This is associated with fewer adverse effects and lower cost than electroejaculation. In addition, collection may take place at home instead of in the operating room.

Artificial insemination

Artificial insemination (AI) involves the placement of sperm directly into the cervix (ie, intracervical insemination [ICI]) or the uterus (ie, intrauterine insemination [IUI]). AI is most useful for couples in whom the postcoital test indicated no sperm, those who have very low sperm density or motility, or those who have unexplained infertility.

IUI allows the sperm to be placed past the inhospitable cervical mucus and increases the chance of natural fertilization. This results in a 4% pregnancy rate if used alone and a pregnancy rate of 8-17% if combined with superovulation. Both processes require semen processing.

Older age in the man has been associated with lower pregnancy rates and higher rates of subsequent spontaneous abortions in patients undergoing IUI.[84, 85] Patients in whom IUI has failed 3-6 times should consider proceeding to IVF.

Assisted reproduction techniques

Patients with severe oligospermia, azoospermia, unexplained infertility, or known defects that preclude fertilization by other means are candidates for assisted reproduction techniques. Assisted reproduction techniques use donated or retrieved eggs that are fertilized by the male partner's sperm or donor sperm. The fertilized embryos are then replaced within the female reproductive tract. These techniques result in a 15-20% delivery rate per cycle and may eventually be successful in 50% of cases. However, the high cost and technical difficulty of the procedures generally preclude their routine use as first-line therapy.

In vitro fertilization

IVF involves fertilization of the egg outside the body and reimplantation of the fertilized embryo into the woman's uterus. Indications for IVF include previous failures with IUI and known conditions of the male or female precluding the use of less-demanding techniques.

IVF generally requires a minimum of 50,000-500,000 motile sperm. Harvesting eggs initially involves down-regulating the woman's pituitary with a GnRH agonist and then performing controlled ovarian hyperstimulation.

Follicular development is monitored by ultrasonographic examination and by checking serum levels of estrogen and progesterone. When the follicles are appropriately enlarged, a transvaginal follicular aspiration is performed.

A mean of 12 eggs are typically retrieved per cycle, and they are immediately placed in an agar of fallopian-tube medium. After an incubation period of 3-6 hours, the sperm are added to the medium using approximately 100,000 sperm per oocyte. After 48 hours, the embryos have usually reached the 3- to 8-cell stage. Two to 4 embryos are usually implanted in the uterus, while the remaining embryos are frozen for future use. Pregnancy rates are 10-45%.

Overall, IVF is a safe and useful procedure. Risks include multiple pregnancies and hyperstimulation syndrome, as well as a slightly higher rate of major birth defects.[86] Additionally, an increased risk of hypospadias occurs in boys (1.5% vs 0.3%), probably because of the increased maternal progesterone used for egg harvesting.[87]

Finally, the use of this technology has led to many ethical issues, such as the fate of embryos after divorce.

Gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT)

These procedures allow the placement of semen (GIFT) or a fertilized zygote (ZIFT) directly into the fallopian tube by laparoscopy or laparotomy. Success rates have been estimated to be 25-30% using these techniques. Unfortunately, these procedures require general anesthesia and have associated risks. Fertilization and implantation within the uterus are not guaranteed, and these procedures cannot be performed in patients with fallopian tube obstruction. GIFT and ZIFT are rarely used as a therapeutic option.

Intracytoplasmic sperm injection

ICSI involves the direct injection of a sperm into an egg under microscopy (see image below). It is indicated in patients in whom more conservative therapies have failed or those with severe abnormalities in which no other treatment would be effective, including patients with sperm extracted directly from the epididymis or testicle.



View Image

Male infertility. Technique of intracytoplasmic sperm injection (ICSI). A micropipette is used to inject a single sperm directly into an egg.

Sperm samples are collected either via masturbation or surgically. Surgical extraction may be more useful in cases of persistent necrozoospermia, due to the high DNA fragmentation rates in ejaculated sperm. Sperm can then be evaluated microscopically for motility, morphology, DNA quality, and/or the ability to bind a hyaluronic acid assay.[88] The embryologist then chooses the most adequate sperm for the procedure.

Oocytes are processed with hyaluronidase to remove the cumulus mass and corona radiata. A micropipette is used to hold the egg while a second micropipette injects the sperm. The oocyte is positioned with the polar body at the 6-o'clock or 12-o'clock position, and the sperm is injected at the 3-o'clock position to minimize the risk of chromosomal damage in the egg. After incubation for 48 hours, the embryo is implanted in the woman.

Van Steirteghem et al reported a 59% fertilization rate and a 35% pregnancy rate with the use of ICSI in 1409 oocytes.[89] Fresh sperm and cryopreserved sperm appear to have similar success rates.[90] In female partners of men with infertility who are undergoing ICSI, diminished ovarian reserve may adversely affect the success of TESE (ie, reduce the clinical pregnancy rate).[79, 80] Some studies also suggest that a direct correlation exists between endometrial thickness and pregnancy rates after ICSI.[91]

The potential complications, ethical issues, and high costs of ICSI must be considered and individualized.

Consultations

Geneticist

A genetics consultation may be indicated in patients with a known or suspected genetic cause of infertility and in patients with nonobstructive azoospermia or severe oligospermia (< 5 million sperm/mL). In addition, in the era of IVF and ICSI, determining the risks of passing on chromosomal abnormalities to a potential offspring is important.

Use a peripheral karyotype and a PCR-based evaluation of the Y chromosome to evaluate for microdeletions. Patients with nonobstructive azoospermia have a 13-17% chance of genetic abnormalities, 4-16% of which are due to Klinefelter syndrome and 9%, to a partial Y deletion.

Patients with CBAVD nearly uniformly have a mutation in the CFTR gene. An estimated 50-82% of men with CBAVD have a genital-only form of CF, which may manifest in patients with only one copy of the abnormal CF gene. In contrast, patients with clinical CF usually have two copies of the abnormal gene.

In men who do have the digestive and pulmonary complications of CF, technology is allowing them to live longer. These men are now candidates for assisted reproductive techniques. The female partner must be evaluated for a CFTR gene mutation before attempted fertilization to determine the risk of producing offspring with CF, which is an autosomal recessive trait.

Endocrinologist

Patients with severe oligospermia or azoospermia should be evaluated with a hormonal evaluation.

Patients with unexplained hypogonadism or hyperprolactinemia should undergo a CT scan or MRI of the sella turcica to evaluate for a pituitary tumor.

Abnormalities may indicate the need for a formal endocrinology consultation.

Diet

See the list below:

Activity

See the list below:

Guidelines Summary

The following guidelines on male infertility are available:

Medication Summary

The goal of pharmacotherapy is to improve sperm count.

Clomiphene (Clomid, Serophene)

Clinical Context:  Stimulates release of pituitary gonadotropins.

Class Summary

These agents cause increased hypothalamic secretion of GnRH owing to blockage of estrogen inhibition.

Bromocriptine (Parlodel)

Clinical Context:  Semisynthetic ergot alkaloid derivative with strong dopamine D2-receptor agonist and partial dopamine D1-receptor effects. Therapeutic range is usually 5-7.5 mg/d. Administer with meals to decrease nausea.

Class Summary

These agents are ergot derivatives and dopamine receptor agonists. They act on postsynaptic dopamine receptors while causing no effect on other anterior pituitary functions. Mimic dopamine action of inhibition of prolactin release.

Menotropins (Pergonal, Repronex)

Clinical Context:  Stimulate spermatogenesis. Contain 75 IU of FSH and 75 IU of LH per vial.

Human chorionic gonadotropin (Novarel, Profasi, Pregnyl)

Clinical Context:  Polypeptide hormone produced by the human placenta. Composed of an alpha and beta subunit. Alpha is identical to LH and FSH. Effects are similar to that of LH (stimulates Leydig cells to produce testosterone). Has other uses and only use in testicular function is described here.

Class Summary

These agents stimulate production of gonadal steroid hormones.

Prognosis

The prognosis of a patient with infertility depends on its underlying cause. The appropriate workup must be performed, and then the appropriate intervention may be used. Prognosis is individualized depending on these results.

Patient Education

Couples should be counseled that the most effective regimen is to perform coitus every 48 hours at mid cycle. For patient education resources, see the Sexual Health Center. Also, see the patient education articles Impotence/Erectile Dysfunction, Erectile Dysfunction FAQs, and Infertility.

Author

Kristen Meier, MD, Resident Physician, Department of Urology, Oakland University William Beaumont School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Chirag N Dave, MD, Physician in Sexual and Male Reproductive Medicine and Urology, Advanced Urology Institute of Georgia

Disclosure: Nothing to disclose.

Richard C Bennett, MD, Assistant Professor of Urology, Oakland University William Beaumont School of Medicine; Urologist, Comprehensive Urology

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Mark Jeffrey Noble, MD, Consulting Staff, Urologic Institute, Cleveland Clinic Foundation

Disclosure: Nothing to disclose.

Chief Editor

Edward David Kim, MD, FACS, Professor of Surgery, Division of Urology, University of Tennessee Graduate School of Medicine; Consulting Staff, University of Tennessee Medical Center

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Endo.

Additional Contributors

Daniel B Rukstalis, MD, Professor of Urology, Wake Forest Baptist Health System, Wake Forest University School of Medicine

Disclosure: Nothing to disclose.

Jonathan Rubenstein, MD, Urologist, Chesapeake Urology Associates

Disclosure: Nothing to disclose.

Kassem Faraj, Oakland University William Beaumont School of Medicine

Disclosure: Nothing to disclose.

Paras Vakharia, PharmD, Medical Student Researcher, Department of Dermatology, Henry Ford Hospital; Medical Student Researcher, Department of Ophthalmology and Department of Radiation Oncology, Oakland University William Beaumont School of Medicine

Disclosure: Nothing to disclose.

Robert E Brannigan, MD, Associate Professor, Department of Urology, Northwestern University, Feinberg School of Medicine

Disclosure: Nothing to disclose.

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Male infertility. Normal male ductal anatomy.

Male infertility. Hypothalamic-pituitary-gonadal axis stimulatory and inhibitory signals. Gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. FSH stimulates the Sertoli cells to facilitate sperm production, while LH stimulates testosterone release from the Leydig cells. Feedback inhibition is from testosterone and inhibin.

Male infertility. Testicular histology magnified 500 times. Leydig cells reside in the interstitium. Spermatogonia and Sertoli cells lie on the basement membrane of the seminiferous tubules. Germ cells interdigitate with the Sertoli cells and undergo ordered maturation, migrating toward the lumen as they mature.

Male infertility. Normal male ductal anatomy.

Male infertility. Varicocele. A - Physical examination revealing the characteristic "bag of worms." B - Anatomy of the dilated pampiniform plexus of veins.

Male infertility. Technique of open vasography: The vas distal to the site of incision is determined to be patent if saline is injected without resistance. Alternatively, radiographic contrast dye is injected through the vas deferens and radiography is performed, or blue dye may be injected and visualized in the urine to confirm patency. A vasovasostomy or vasoepididymostomy may then be performed at this level.

Male infertility. Technique of microscopic varicocelectomy. The individual veins of the pampiniform plexus are isolated (top) and ligated, taking care to preserve the testicular artery (bottom) isolated using the intraoperative Doppler.

Male infertility. Technique of vasovasostomy: Upper left is confirmation of sperm from the proximal vas deferens, proving proximal patency. Upper right is the inner layer anastomosis using interrupted #10-0 Prolene. Lower left is the inner layer anastomosis completed. Lower right is the outer layer anastomosis using #9-0 Prolene completed.

Male infertility. Technique of vasoepididymostomy. Left upper is confirmation of mature sperm in epididymis. Right upper is the inner layer anastomosis of the end of the vas to the side of the epididymal tubule using interrupted #10-0 Prolene. Left lower is the inner layer completed. Right lower is the outer layer anastomosis using interrupted #9-0 Prolene completed.

Male infertility. Technique of intracytoplasmic sperm injection (ICSI). A micropipette is used to inject a single sperm directly into an egg.

Male infertility. Hypothalamic-pituitary-gonadal axis stimulatory and inhibitory signals. Gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. FSH stimulates the Sertoli cells to facilitate sperm production, while LH stimulates testosterone release from the Leydig cells. Feedback inhibition is from testosterone and inhibin.

Male infertility. Testicular histology magnified 500 times. Leydig cells reside in the interstitium. Spermatogonia and Sertoli cells lie on the basement membrane of the seminiferous tubules. Germ cells interdigitate with the Sertoli cells and undergo ordered maturation, migrating toward the lumen as they mature.

Male infertility. Normal male ductal anatomy.

Male infertility. Varicocele. A - Physical examination revealing the characteristic "bag of worms." B - Anatomy of the dilated pampiniform plexus of veins.

Male infertility. Technique of open vasography: The vas distal to the site of incision is determined to be patent if saline is injected without resistance. Alternatively, radiographic contrast dye is injected through the vas deferens and radiography is performed, or blue dye may be injected and visualized in the urine to confirm patency. A vasovasostomy or vasoepididymostomy may then be performed at this level.

Male infertility. Technique of microscopic varicocelectomy. The individual veins of the pampiniform plexus are isolated (top) and ligated, taking care to preserve the testicular artery (bottom) isolated using the intraoperative Doppler.

Male infertility. Technique of vasovasostomy: Upper left is confirmation of sperm from the proximal vas deferens, proving proximal patency. Upper right is the inner layer anastomosis using interrupted #10-0 Prolene. Lower left is the inner layer anastomosis completed. Lower right is the outer layer anastomosis using #9-0 Prolene completed.

Male infertility. Technique of vasoepididymostomy. Left upper is confirmation of mature sperm in epididymis. Right upper is the inner layer anastomosis of the end of the vas to the side of the epididymal tubule using interrupted #10-0 Prolene. Left lower is the inner layer completed. Right lower is the outer layer anastomosis using interrupted #9-0 Prolene completed.

Male infertility. Technique of intracytoplasmic sperm injection (ICSI). A micropipette is used to inject a single sperm directly into an egg.

Analysis Finding Conclusion/Further investigation
Ejaculate volumeLow (< 1.5 mL)Postejaculation urine (retrograde ejaculation)



TRUS (absence of vas deferens)



Hormonal evaluation (hypogonadism)



High (>5 mL)Likely contaminant
Semen qualityDoes not coagulateTRUS (ejaculatory duct obstruction)
Does not liquefyHormonal analysis
Sperm densityOligospermia (< 20 million per mL)



Severe oligospermia (< 5 million per mL)



TRUS (partial ejaculatory duct obstruction)



Antisperm antibody evaluation



Hormonal analysis



Physical examination for varicocele



AzoospermiaSperm centrifuged to verify azoospermia



Postejaculation urine (retrograde ejaculation)



Hormonal evaluation



Testicular biopsy (testicular failure)



TRUS (ejaculatory duct obstruction)



MotilityDecreasedAntisperm antibodies



Physical examination for varicocele



*All semen analyses with abnormal results should be repeated.