Male Infertility Clinical Presentation

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:

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

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] :

• Diabetes may cause autonomic neuropathy, neurogenic impotence, and retrograde ejaculation
• Obesity alters hormonal metabolism, leading to increased peripheral conversion of testosterone to estrogen and decreased luteinizing hormone (LH) pulse amplitude, and has been linked with reduced sperm concentration ^[8]
• Sickle cell disease may lead to direct testicular ischemia and damage
• Patients with sickle cell disease or thalassemia may have infertility due to hemosiderosis from multiple blood transfusions
• Almost all males with cystic fibrosis have congenital bilateral absence of the vasa deferens (CBAVD). Approximately 70% of males identified with CBAVD and no evidence of CF will carry an identifiable abnormality of the CFTR gene ^{[9, 10]}
• Chronic kidney disease leads to hypogonadism and feminization
• Liver disease may result in decreased male secondary sexual characteristics, testicular atrophy, and gynecomastia due to increased estrogen levels
• Hemochromatosis leads to hypogonadism and signs of androgen deficiency without gynecomastia and is associated with decreased estradiol levels
• Postpubertal mumps may lead to testicular atrophy
• Sexually transmitted diseases and tuberculosis can cause obstruction of the vas deferens or epididymis
• Mycoplasma fastens itself to sperm, decreasing sperm motility
• 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 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:

• Spironolactone, cyproterone, ketoconazole, and cimetidine have antiandrogenic properties
• Tetracycline lowers testosterone levels 20% ^[16]
• Nitrofurantoin suppresses spermatogenesis
• Sulfasalazine leads to a reversible decrease in sperm motility and density
• Colchicine, methadone, methotrexate, phenytoin, thioridazine, and calcium channel blockers have all been associated with infertility

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:

• Many pesticides have estrogen-like effects.
• Dibromochloropropane (DBCP) is a nematocide widely used in agriculture that causes azoospermia without recovery, by an unknown mechanism.
• Lead exposure depresses the hypothalamic-pituitary axis.
• Carbon disulfide exposure from the rayon industry leads to semen, pituitary, and hypothalamic changes.
• Heat exposure, as seen in workers in the steel and ceramic industries, decreases spermatocyte maturation.

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]

 

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:

• Primary testicular failure
• Klinefelter syndrome
• Endocrinopathies
• Postpubertal mumps
• Liver disease
• Myotonic dystrophy

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.

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 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:

• Granulomatous disease – Leprosy and sarcoidosis may infiltrate the testicle
• Sickle cell disease – Sickling of cells within the testis leads to microinfarcts
• Excessive use of alcohol, cigarettes, caffeine, or marijuana

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:

• Diabetic neuropathy
• Bladder neck surgery
• Retroperitoneal lymph node dissection
• Transurethral prostatectomy
• Colon or rectal surgery
• Multiple sclerosis
• Spinal cord injury
• Use of medicines such as alpha-antagonists

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

• Compatible medical or surgical history
• Low ejaculate volume
• Presence of 10-15 sperm per high-power field (HPF) in the postejaculatory urine