Gonadal and sexual functions are mediated by the hypothalamic-pituitary-gonadal axis, a closed-loop system with feedback control from the testicles (see Image 1). The hypothalamus, the primary integration center, responds to a variety of signals from the CNS, pituitary, and testicles to secrete releasing factors, such as gonadotropin releasing hormone (GnRH), to modulate pituitary function. Hypothalamic input from the CNS includes signals from the amygdala, hippocampus, and mesencephalon, which respond to various internal and external stimuli.

GnRH is released from the medial basal hypothalamus in a pulsatile pattern approximately every 70-90 minutes. It then travels down the portal system to the anterior pituitary, where it stimulates the release of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The half-life of GnRH is 2-5 minutes. Its diurnal release may be due to melatonin from the pineal gland. GnRH release is inhibited by negative feedback signals from the testicle, specifically testosterone and inhibin. Additionally, corticotropin-releasing hormone (CRH), released during stress, and opiates, both internal and external, down-regulate GnRH secretion. The body responds to illness and stress by a decreased production of gonadotropins.

The pituitary gland, which lies on a stalk beneath the hypothalamus in the sella turcica, contains the gonadotropic cells that produce both FSH and LH. These are glycopeptides with a molecular weight of 10,000 daltons. They are made up of an alpha chain that is identical with that of human chorionic gonadotropin (HCG) and thyroid-stimulating hormone (TSH) and 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. This is clinically significant and is used in the medical treatment of prostate cancer and endometriosis.

After release into the systemic circulation, FSH and LH 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. Gonadotropin release is modulated by a variety of 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.

The pituitary also secretes prolactin, which normally functions to stimulate breast development and lactation. Prolactin release is held in check by the hypothalamic production of dopamine. The hypothalamus produces thyrotropin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP). Both stimulate 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.

The testicle (Image 2), the end organ of the axis, contains the Leydig cells and the Sertoli cells, which respond to LH and FSH, respectively, by the secretion of testosterone (Leydig cells) and maturation of the germ cells (Sertoli cells). The testicles are derived embryologically from the genital ridge near the kidneys, and they descend to the scrotum during gestation. The intermesenteric nerves of the renal plexus innervate the testicle, and the blood supply is from the internal spermatic artery, the artery to the vas deferens, and from the external spermatic (cremasteric) artery.

The thick tunica albuginea covers the testes and provides septae that divide it into approximately 200-350 pyramids. 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. Seminiferous tubules are made up of Sertoli cells and germ cells, and they are surrounded by peritubular and myoid cells.

Sertoli cells, which rest on the basement membrane of the seminiferous tubules, serve mainly to support, nourish, and protect the developing germ cells. Histologically, they are columnar, with irregular basal nuclei that have prominent nucleoli and fine chromatin. Sertoli cells additionally serve as the blood-testis barrier by their unique tight junctions that divide the seminiferous tubules into a basal and abluminal compartment. This provides a microenvironment that facilitates spermatogenesis and maintains the germ cells in an immunologically privileged location. Sertoli cells secrete inhibin, a feedback molecule, and androgen-binding protein, which helps modulate androgen activity in the seminiferous tubules. Normal Sertoli cell function is modulated by FSH, a high level of intratesticular testosterone, and signals from elsewhere in the testicle such as the peritubular myoid cells bordering the seminiferous tubules.

The Leydig cells are located in the interstitium between the seminiferous tubules and serve primarily to secrete testosterone in response to LH. Histologically, Leydig cells are polygonal with eosinophilic cytoplasm. Occasionally, crystalloids of Reinke may be observed in the cytoplasm after puberty. LH binds to a G protein–coupled receptor on the Leydig surface and up-regulates the enzymes involved in the conversion of cholesterol to testosterone.

Testosterone is secreted in a diurnal pattern, peaking early in the morning. 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. A high level of intratesticular testosterone is necessary for normal spermatogenesis. Testosterone and estradiol also function as feedback inhibitors of gonadotropin release. These steroids exert their effect by crossing the plasma membrane and binding to specific receptors in the cytosol and nucleus.

Normal spermatogenesis requires complex interactions between the Sertoli cells, Leydig cells, and germ cells. Germ cells, precursors to spermatozoa, interdigitate with Sertoli cells. They are derived from the gonadal ridge and migrate as gonadocytes to the testicle before testicular descent. After puberty, because of stimulation by FSH, these cells become spermatogonia and undergo an ordered maturation to become spermatozoa. The entire process of development from spermatogonium to spermatid requires 74 days and is described in 14 steps; as they mature, the developing spermatids progress closer to the lumen of the seminiferous tubule.

Spermatogonia, which rest on the basement membrane, contain dense nuclei and prominent nucleoli. Three types are described. The stem cell, also known as A dark (Ad), divides to create more Ad cells (stem cell renewal) and differentiates into daughter A pale (Ap) cells every 16 days. These Ap cells mature into B spermatogonia, which are committed to becoming spermatids. The B cells 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 (R), leptotene (L), zygotene (Z), and pachytene (P) stages to become secondary spermatocytes (Sa). During this time, the cells cross from the basal to the abluminal 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. A total of 4 spermatids are made from each spermatocyte.

Next, the spermatids undergo the process of spermiogenesis through the successive Sb1, Sb2, Sc, Sd1, and Sd2 stages. This involves casting 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, contains enzymes necessary to penetrate the egg. It surrounds the nucleus anteriorly. The mature spermatid is adjacent to the lumen and contains dark chromatin with an oval-shaped nucleus, a mid piece with helically arranged mitochondria, a principal piece, and an end piece. The axoneme contains all the enzymes and structural proteins necessary for adenosine triphosphate (ATP) conversion to energy to propel the tail, which are cilia with a 9+2 microtubule core.

After their release from the Sertoli cells into the lumen of the seminiferous tubules, the spermatids enter the tubuli recti, rete testis, ductuli efferentes, and, finally, the epididymis (see Image 3). 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. In addition, various substances are secreted for sperm nutrition and protection such as glycerophosphorylcholine, carnitine, and sialic acid.

During ejaculation, the sperm enter the vas deferens, a 30- to 35-cm long muscular conduit of wolffian duct origin. The vas is divided into the convoluted, scrotal, inguinal, retroperitoneal, and ampullary regions, and it receives its blood supply from the inferior vesicle 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, proceeding forward through the prostate parenchyma as the ejaculatory duct. The ejaculatory duct empties next to the verumontanum. Bladder neck closure during ejaculation is vital to ensure antegrade ejaculation. The semen is propelled forward by the rhythmic contractions of the smooth muscle surrounding the ducts and by the bulbourethral muscles and other pelvic muscles.

Semen is composed of secretions not only from the testis and epididymis but also from the bulbourethral (Cowper) glands, the glands of Litre (periurethral), the seminal vesicles, and the prostate. Usual ejaculate volume is 1.5-5 mL, and the pH is 7.05-7.80. The seminal vesicles produce 40-80% of the semen volume. Secretions include 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. A fructose level of less than 120 mg/dL is often due to an obstruction of the ejaculatory ducts or absence of the seminal vesicles, especially when associated with a low ejaculate volume and a thin, watery consistency. 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 ordered sequence of release is important for appropriate functioning. The prostate and vas provide most of the early ejaculate, which is rich in sperm. Cowper glands, which are found in the membranous urethra, and the glands of Litre each provide 2-5% (0.1-0.2 mL) of the total ejaculate volume, mainly to lubricate the urethra and to buffer the acidity of the residual urine. Finally, the testicular-epididymal component, including spermatozoa, comprises 5% of the ejaculate volume.

For conception, sperm must reach the cervix and penetrate the cervical mucus, migrate up the uterus to the fallopian tube with the oocyte, and penetrate the zona pellucida and cell membrane. The cervical mucus changes consistency during the ovulatory cycle, being most hospitable and easily penetrated at mid cycle. The sperm must not only survive within the female genital tract but also be able to migrate to the site of fertilization, 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. After fertilization, implantation may then take place in the uterus. Problems with any of these steps may lead to infertility.

Frequency:

• In the US: 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. For American men, the risk correlates to approximately 1 chance 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.

• Internationally: 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.

  Recent debate has occurred in the literature regarding a poorer semen quality, decreased sperm numbers, and decreased fertility in men today compared to that of 50 years ago, citing a decrease in sperm counts from an average of 113 million/mL in 1940 to 66 million/mL in 1990. 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 symptom have a serious underlying medical disease. Ruling out life-threatening or life-altering conditions in these patients during the workup is important. Examples include pituitary adenomas, hormonally active tumors, testicular cancer, liver and renal failure, and cystic fibrosis (CF).

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 an obvious cause in one partner exists, it seems reasonable to perform a thorough evaluation of both partners for completeness. 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, and a loss of 50% of Leydig cells occurs by age 60 years. Despite this, aging men may achieve similar fertility rates as younger men, although conception often takes longer.

• A paradigm shift exists regarding the timing of the initial workup for infertility. Traditionally, couples are evaluated only after a 1-year trial. Because couples start family planning later in life, infertility is now commonly evaluated upon initial presentation. In part, this is because of advanced maternal ages, couples' anxiety, and the availability of more reliable and cost-effective treatment options.

History: The initial step in the evaluation of an infertile male is to obtain a thorough medical and urologic history. Important points include the duration of infertility, previous fertility in the patient and the partner, and prior workup evaluations and treatments. The couple should be asked specifically about their sexual habits. This includes their level of education regarding the optimal timing of intercourse and the use of potentially spermatocytic 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 the age 9 years in men, 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 the secretion of testosterone due to hypothalamic, pituitary, or primary testicular insufficiency or end organ androgen insensitivity.

• Childhood urological disorders or surgery

   

  • Both unilateral and bilateral cryptorchidism are associated with a decrease in sperm production and semen quality, regardless of the timing of orchidopexy.

     

  • Patients with hypospadias may not place the semen at the cervical os.

     

  • 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

   

  • Diabetes may cause autonomic neuropathy, neurogenic impotence, and retrograde ejaculation.

     

  • Obesity causes a change in hormonal metabolism with an increased peripheral conversion of testosterone to estrogen and decreased LH pulse amplitude.

     

  • Sickle cell disease may lead to sickling and, therefore, direct testicular ischemia and damage.

     

  • Infertility may be secondary to hemosiderosis due to multiple transfusions in patients with sickle cell disease or thalassemia.

     

  • Chronic renal failure leads to hypogonadism and feminization because of primary testicular failure.

     

  • Liver disease leads to decreased libido, impotence, decrease in male secondary sexual characteristics, testicular atrophy, and gynecomastia because of increased estrogen levels.

     

  • Hemochromatosis leads to hypogonadism and signs of androgen deficiency without gynecomastia, and it is associated with decreased estradiol levels.

     

  • Postpubertal mumps may lead to testicular atrophy and infertility.

     

  • Sexually transmitted diseases and tuberculosis can cause obstruction of the vas deferens or epididymis.

     

  • Mycoplasma fastens itself to sperm, causing decreased motility.

     

  • Smallpox, prostatitis, orchitis, seminal vesiculitis, and urethritis may lead to obstructive azoospermia.

• Acute and chronic medical illnesses

   

  • Patients should be asked about recent acute febrile illnesses, which may cause a temporary suppression of gonadotropins. The decrease in sperm production may not be realized until 1-3 months later in the semen analysis.

     

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

     

  • Chronic medical illnesses may lead to end organ failure by directly suppressing sex hormone levels and sperm production.

• Sexual history

   

  • The frequency, timing, and methods of coitus and knowledge of the ovulatory cycle should be elicited.

     

  • Many lubricants, such as Surgilube, Keri lotion, KY Jelly, and even saliva are spermatotoxic and should be avoided. Lubricants such as egg whites, peanut oil, vegetable oil, and petroleum jelly are not known to be spermatotoxic but still should only be used in the smallest amounts possible.

     

  • Studies show that the optimal timing for intercourse is every 48 hours at mid cycle.

• Testicular cancer

   

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

     

  • Oligospermia is observed in more than 60% of patients at the time of diagnosis of testicular cancer.

     

  • Germ cell tumors are believed to share common etiological factors with testicular dysfunction, such as testicular dysgenesis, androgen insensitivity, and cryptorchidism. This is known because of an increased incidence of contralateral abnormalities of spermatogenesis in patients with testicular cancer and the fact that sperm function remains impaired even after orchiectomy.

• Treatment for testicular cancer

   

  • 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. Chemotherapy is also mutagenic, so sperm should be donated before treatment or attempts at conception should be postponed to more than 1 year after treatment.

     

  • Retroperitoneal lymph node dissection (RPLND) may result in impaired emission (of semen into the urethra) and/or retrograde ejaculation.

     

  • The effects of radiation depend on the total dose delivered and the developmental stage of germ cells. Radiation therapy (XRT) 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 observed 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 XRT 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 leading 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

   

  • Studies have linked smoking to a decreased libido, while both cigarettes and marijuana lead to a decrease in sperm density, motility, and morphology.

     

  • Alcohol has been shown to produce both an acute and a chronic decrease in testosterone secretion.

     

  • Emotional stress causes a blunted 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 that wearing constrictive underwear, or "briefs," causes decreased fertility. Even with an elevation in temperature of 0.8-1.0 degrees caused by wearing constrictive underwear, no changes in sperm parameters, no decrease in spermatogenesis, and no changes in sperm function are observed.

• Medicines

• Many therapeutic drugs are associated with decreased sperm production.

   

• Spironolactone, cyproterone, ketoconazole, and cimetidine have antiandrogenic properties.

   

• Tetracycline lowers testosterone levels 20%, while nitrofurantoin depresses spermatogenesis.

   

• Sulfasalazine used for the treatment of ulcerative colitis leads to decreased sperm motility and density, which is reversible.

   

• Infertility has also been associated with colchicine, methadone, methotrexate, phenytoin, thioridazine, and calcium channel blockers.

• Family history

• Congenital midline defects, cryptorchidism, hypogonadotropism, and testicular atrophy in family members may be a sign of a congenital disease.

   

• A history of CF or hypogonadism should be elicited.

• Respiratory disease

• Infertility and recurrent respiratory infections may be due to immotile cilia syndrome. Immotile cilia may manifest as an isolated disease or as 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 inspissated material in the epididymis causing obstruction.

• Environmental and/or occupational exposure

• Many pesticides have estrogenlike effects.

   

• Dibromochloropropane (DBCP) is a nematocide widely used in agriculture that causes azoospermia without recovery because of an unknown mechanism.

   

• Lead affects the hypothalamic-pituitary axis, leading to suppression of testosterone.

   

• Carbon disulfide exposure from the rayon industry leads to semen, pituitary, and hypothalamic changes.

   

• Heat, such as in the steel and ceramic fields, affects spermatocyte maturation.

• Spinal cord injury

• Severe spinal cord injury causes infertility by a variety of mechanisms. Many patients are unable to ejaculate. Fortunately, electroejaculation or sperm retrieval techniques may be used with some success.

   

• For unknown reasons, patients with a spinal cord injury often have a gradual decline in their semen quality. Within a year after injury, semen analysis often reveals dead sperm with signs of neutrophil infiltration. This is thought to be due to accessory gland dysfunction rather than lack of ejaculation and atrophy.

• Epididymal and testicular factors appear to play a role, although the most severe dysfunction seems to come from prostatic and seminal vesicle dysfunction.

• In patients with spinal cord injury, sperm parameters from the vas deferens show 54% motility and 74% viability, while only 14% motility and 26% viability is observed in ejaculated sperm. These are both much lower than that of control subjects.

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 to each other.

   

• A Prader orchidometer or ultrasound may be used to estimate the testicular volume, which is usually 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.

   

• Testicular atrophy may be observed in primary testicular failure, Klinefelter syndrome, endocrinopathies, postpubertal mumps, liver disease, and myotonic dystrophy.

   

• Swelling with pain is indicative of 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 CF gene, 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 4). 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.

   

• 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 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 posttesticular.

Pretesticular causes of infertility

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

Hypothalamus

Disorders of the hypothalamus lead to hypogonadotropic hypogonadism. GnRH is not secreted, and no release of LH and FSH from the pituitary occurs. Ideally, patients respond to replacement with exogenous GnRH or 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 10,000-60,000 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 a normal height, but it does not improve spermatogenesis because of insufficient intratesticular testosterone levels. Exogenous testosterone should never be administered in an attempt to boost sperm production because it actually leads to decreased intratesticular testosterone levels. Pulsatile GnRH and HCG have been used but result in only 20% achieving complete spermatogenesis.

• Prader-Willi syndrome: Patients have characteristic obesity, mental retardation, 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: A variety of other lesions and diseases, such as CNS tumors, temporal lobe seizures, and many drugs (eg, dopamine antagonists) may interrupt the hypothalamic-pituitary axis at the hypothalamus.

   

Pituitary failure may be congenital or acquired, caused by tumor, infarction, radiation, infection, or granulomatous disease. Functional pituitary tumors may lead to unregulated gonadotropin release or prolactin excess. Even nonfunctional pituitary tumors can lead to pituitary failure by compressing the pituitary stalk or the gonadotropic cells, interrupting the proper chain of signals.

• Prolactinoma

   

  • A prolactin-secreting adenoma is the most common functional pituitary tumor. Because prolactin stimulates breast development and lactation, patients presenting with infertility often have gynecomastia and galactorrhea. Loss of peripheral visual fields bilaterally may be due to compression of the optic chiasm.

     

  • A prolactin level greater than 150 mcg/L is usually indicative of an 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, a dopamine agonist, is used to suppress prolactin levels and is the therapy of choice for microprolactinomas. Cabergoline is also a treatment option. Some men respond not only with an increase in testosterone level but 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 for patients with visual field defects or those who do not tolerate bromocriptine.

• Isolated LH deficiency (fertile eunuch): LH is decreased while FSH levels are within the reference range. Patients have eunuchoidal body habitus, large testis, and a low ejaculatory volume. 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 or exogenous FSH.

   

• Thalassemia: Patients with thalassemia have ineffective erythropoiesis and undergo multiple blood transfusions. Excess iron is 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.

   

The hypothalamus-pituitary axis may be interrupted by hormonally active peripheral tumors or other exogenous factors.

• Cortisol excess or deficiency: Excess cortisol may be produced by adrenal hyperplasia, adenomas, carcinoma, congenital adrenal hyperplasia (CAH), or lung tumors. A variety of enzyme defects leads to CAH. The most common is 21-hydroxylase deficiency. 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 occasional bilateral testicular rests. Screening tests include increased plasma 17-hydroxylase and urine 17-ketosteroids. High cortisol levels, which cause negative feedback on the pituitary to decrease LH release, may be observed in Cushing syndrome.

   

• Estrogen: High estrogen levels may be secondary to Sertoli cell tumors, Leydig tumors, liver failure, or massive obesity. Estrogen causes negative feedback on the pituitary gland.

   

• Iatrogenic causes: High cortisol levels due to steroid therapy for ulcerative colitis, asthma, arthritis, or organ transplant may lead to inhibition of hypothalamic GnRH 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 to 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.

• 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, two thirds of which is of maternal origin; mosaic forms are due to nondisjunction following fertilization. The only known risk factor 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 therapy may suppress any underlying sperm production so this is never a mode of treatment for azoospermia.

   

• Physical examination in these patients reveals gynecomastia, small testis, and eunuchoid body proportions because of delayed puberty. 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. 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 (PGD).

• 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 is often associated with aggression and criminal 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, shieldlike chest, lymphedema of hands and feet, cardiovascular abnormalities, and cubitus valgus. Leydig cell function is impaired, and most patients are infertile because of primary testicular failure.

   

• Mixed gonadal dysgenesis (45,X/46,XY): Patients have ambiguous genitalia, a testis on one side, and a streaked gonad on the other.

   

• 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 new microdeletions have been implicated as a significant cause of infertility. These microdeletions are not observed on regular karyotype; 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). These deletions are observed in 3-19% of patients with idiopathic infertility and 6-14% of patients with oligospermia, although up to 7% of patients with other known causes of infertility may also be found to have a deletion. Patients with azoospermia or severe oligospermia seeking assisted reproductive techniques should be screened.

   

• Bilateral anorchia (vanishing testis syndrome): Patients have a normal male karyotype (46,XY) but are born without testis bilaterally. The male phenotype proves that androgen was present in utero. Potential causes are unknown, but it 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 by 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 are usually elevated.

   

• Myotonic dystrophy: This is an autosomal dominant defect in the dystrophin gene causing 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.

   

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

• Varicocele

• A varicocele is defined as a dilation of the veins of the pampiniform plexus of the scrotum. Although varicoceles are present in 15% of the male population, they have been associated with and implicated as a factor responsible for male infertility in 30-35% of infertile men and the cause of 75-85% of secondary infertility. Varicoceles are observed more commonly on the left side than the right. Those 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. Varicoceles may lead to impaired testicular spermatogenesis and steroidogenesis. Investigators have implicated an increased intratesticular temperature, reflux of toxic metabolites, and/or germ cell hypoxia as potential causes of these changes, and this appears to be progressive over time.

   

• Patients with a grade 2-3 varicocele (visible or palpable) associated with infertility should have the varicocele repaired. After repair, 40-70% of patients have improved semen parameters, while 40% are able to achieve a pregnancy without other intervention, making this the most common surgically correctable cause of male infertility. Those with a varicocele diagnosable only on scrotal ultrasonography will likely not benefit from repair. Adolescents with a varicocele and testicular atrophy or lack of growth should similarly have a repair. Controversy exists regarding whether to routinely repair an adolescent's varicocele if it is not associated with testicular atrophy.

• Cryptorchidism: An estimated 3-4% of full-term males are born with an undescended testicle; however, less than 1% remain undescended by the age of 1 year. Risks for cryptorchidism include family history and prematurity. It may be observed as part of syndromes such as prune belly syndrome. Patients have an increased risk of infertility, despite orchidopexy. The higher and longer the testicle resides outside the scrotum, the greater the likelihood of damage to the seminiferous tubules. 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 present with small- to normal-sized testes and azoospermia. Secondary sex characteristics are normal. Histology reveals seminiferous tubules lined by Sertoli cells and a normal interstitium, although no germ cells are present.

   

• Chemotherapy: Chemotherapy is often most toxic to actively dividing cells, eg, the spermatogonia and spermatocytes. Germ cells up to the preleptotene stage are especially at risk. The most toxic drugs are the alkylating agents such as cyclophosphamide. Treatment for Hodgkin disease 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. When stem cells remain viable, patients may regain fertility within several years. Patients are advised to avoid conception for 6 months to 2 years because of the possibility of chromosomal aberrations in their sperm caused by the mutagenic properties of XRT. Even with the testis shielded, XRT below the diaphragm potentially leads to infertility because of the release of reactive oxygen free radicals.

   

• Orchitis: The most common cause of acquired testicular failure in adults is viral orchitis, usually caused by the mumps virus, echovirus, or group B arbovirus. Of adults with mumps, 25% develop orchitis; two thirds of cases are unilateral orchitis, and one third of cases are bilateral. Orchitis develops within a few days after the onset of the parotid gland inflammation, but orchitis may precede parotid gland inflammation. The virus either directly affects the seminiferous tubules or indirectly causes ischemic damage because of the intense swelling of the testicle and subsequent 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.

   

• Granulomatous disease: Leprosy and sarcoidosis may infiltrate the testicle and lead to testicular failure.

   

• Sickle cell disease: Sickling of cells within the testis leads to microinfarcts and secondary testicular failure.

   

• Other causes: Use of alcohol, cigarettes, caffeine, and marijuana may lead to testicular failure.

   

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

   

Posttesticular causes of infertility

Posttesticular causes of infertility include problems with sperm transportation through the ductal system (congenital or acquired). Genital duct obstruction is a potentially curable cause of infertility, and it 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 DES during pregnancy. A newly described entity called 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 congenital bilateral absence of the vas deferens. The cystic fibrosis transmembrane regulator (CFTR) protein plays a role in mesonephric duct development during early fetal life, so these patients must be evaluated for urinary tract abnormalities using renal ultrasonography or similar imaging tests. Patients are candidates for assisted reproduction techniques after appropriate genetic screening in the partner.

• 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 in the vas deferens, leading to obstruction of sperm transportation. 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.

• Antisperm antibodies: Antisperm antibodies bind to sperm and impair motility. They may lead to clumping as well. This can impair movement through the female reproductive tract and interaction with the oocyte.

• Immotile cilia syndrome: This is isolated or 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. Patients experience sinusitis, bronchiectasis, and infertility.

• Ejaculatory duct obstruction: Complete and partial ejaculatory duct obstruction has been implicated as causing less than 1-5% of male infertility. Patients may have a normal, palpable vas deferens bilaterally with a decreased ejaculate volume, hemospermia, and painful ejaculation. Causes include cysts (midline and eccentric), ductal calcification and stones, postinfectious, and postoperative. Transrectal ultrasound (TRUS) is the least invasive method for evaluation, but not all patients have enlarged seminal vesicles. Seminal vesicle aspiration or a dynamic test, such as injection of indigo carmine into the seminal vesicle or ejaculatory duct, may be necessary for diagnosis.

• Retrograde ejaculation: This is caused by an open bladder neck during ejaculation. Retrograde ejaculation may be due to causes such as diabetes, bladder neck surgery, RPLND, alpha-antagonists, transurethral prostatectomy (TURP), colon or rectal surgery, multiple sclerosis, or spinal cord injury. Diagnosis is made by observing 10-15 sperm per high-power field (HPF) in the postejaculatory urine.

	DIFFERENTIALS	Section 4 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Adrenal Adenoma
Adrenal Carcinoma
C-11 Hydroxylase Deficiency
C-17 Hydroxylase Deficiency
Cannabis Compound Abuse
Chlamydial Genitourinary Infections
Cryptorchidism
Follicle-Stimulating Hormone Abnormalities
Growth Hormone Deficiency
Growth Hormone Replacement in Older Men
Gynecomastia
Hematospermia
Hemochromatosis
Infertility
Intestinal Radiation Injury
Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism
Luteinizing Hormone Deficiency
[Luteinizing Hormone-Releasing Hormone Deficiency]

Lymph Node Dissection, Retroperitoneal
[Open Prostatectomy]

Prostatitis, Bacterial
Scrotal Trauma
Sertoli-Cell-Only Syndrome
Teratology and Drug Use During Pregnancy
Testicular Choriocarcinoma
Testicular Seminoma
Testicular Torsion
Testicular Tumors: Nonseminomatous
Tuberculosis
Urethral Strictures
Urethral Trauma
Urethritis
Urinary Tract Infection, Males
Varicocele
Vasovasostomy and Vasoepididymostomy