Infertility, Male

INTRODUCTION

Background: Infertility is defined as the inability to achieve pregnancy after one year of unprotected intercourse. An estimated 15% of couples meet this criterion and are considered infertile. Historically, the workup for the infertile couple focused primarily on conditions of the female. Conditions of the male are estimated to account for nearly 30% of infertile couples, and conditions of both the female and the male account for another 20%. Conditions of the male that affect fertility are still underdiagnosed and undertreated.

In general, causes of infertility in men can be explained by deficiencies in ejaculate volume, sperm concentration (eg, oligospermia, too few sperm, azoospermia, no sperm in the ejaculate), sperm motility, or sperm morphology. This general division allows an appropriate workup of potential underlying causes of infertility and helps define a course of action for treatment. The initial evaluation of the male patient should be rapid, noninvasive, and cost-effective. Nearly 70% of conditions causing infertility in men can be diagnosed by history, physical examination, testicular volume estimation, and hormonal and semen analysis. A rational approach is necessary to perform the appropriate workup and to choose the best treatment options for the couple.

A variety of treatments exist for the infertile couple, which range from optimizing one's current semen parameters with medical therapy to minor surgical procedures and finally to complex sperm retrieval and assisted reproduction techniques. Technological advancements in assisted reproduction make it possible to conceive a child with as little as one viable sperm and one egg. While the workup traditionally has been delayed until a couple has failed 12 months of attempting to conceive, beginning the workup at the first visit is now recommended because of a recent trend towards delaying family planning. The aim of this chapter is to summarize current knowledge of causes of infertility in men and to describe its workup and treatment.

Pathophysiology: The physiology of normal spermatogenesis, ejaculation, and fertility must be understood prior to performing a thorough workup of the infertile man. This includes a knowledge of the hypothalamic-pituitary-testicular (the integration system controlling sperm and testosterone production), the embryology and physiology of the testis and accessory glands, and the process of fertilization.

CLINICAL

History: The initial step in the evaluation of an infertile male is to perform a thorough medical and urologic history. This should focus on the duration of infertility, previous fertility in the patient or 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, galactorrhea, visual field defects, and sudden loss of libido can all be due to pituitary tumors. 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 of 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.

    　

  • A V-Y plasty of the bladder neck 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 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 due to primary testicular failure.

    　

  • Liver disease leads to decreased libido, impotence, decrease in 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 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, K-Y 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 cancers

  　

  • 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 also is mutagenic, so sperm should be donated before treatment or more than one 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 than1 Gy, sperm production may return in 9-18 months, while it may take 4-6 years to recover 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 normal FSH 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, or release of substances by the tumor because decreased sperm counts were observed even before surgery and did 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 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 constrictive underwear or "briefs" cause decreased fertility. Even with an elevation in temperature of 0.8-1.0 degrees wearing constrictive underwear, no changes in sperm parameters, no decrease in spermatogenesis, and no change in sperm function were observed.

• Medicines

• Many therapeutic drugs are associated with a decreased sperm production.

  　

• Spironolactone, cyproterone, ketoconazole and cimetidine all 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 also has been associated with colchicine, methadone, methotrexate, phenytoin, thioridazine, and calcium channel blockers.

• Family history

• Congenital midline defects, cryptorchidism, hypogonadotropinism, 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 present 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, presence of only one copy may lead to CVABD.

  　

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

• Environmental/occupational exposure

• Many pesticides have estrogenlike effects.

  　

• Dibromochloropropane (DBCP) is a nematocide widely used in agriculture that causes azoospermia without recovery due to 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 controls.

Physical: The physical exam 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 take place in a warm room with the patient relaxed. The testicles should be palpated individually between the thumb and first two fingers. The examiner should note the presence, size, and consistency of the testicles, and each should be compared to the other.

  　

• A Prader orchidometer or ultrasound may be used to estimate the testicular volume, which is usually greater than 20 cc.

  　

• 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 whites and 34 mm in African Americans. Testes in Japanese men are typically smaller than that of whites.

  　

• 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, 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" should alert one to the possibility of a CF gene mutation.

  　

• A thickened, nodular vas deferens may be observed in 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 Picture 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 should alert the examiner to 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 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 exam

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

• The seminal vesicles usually are not palpable.

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

• Body habitus

• An 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 exam 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 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 is not always the case.

  　

• 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 it is estimated to be present in 1 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 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 are characterized by obesity, mental retardation, small hands and feet, and hypogonadotropic hypogonadism due to a GnRH deficiency. It is caused by a disorder of genomic imprinting with deletions of paternally derived chromosome 15q11-13.

  　

• Laurence-Moon-Biedl syndrome: Patients with this syndrome have retinitis pigmentosa and polydactyly. Infertility is due to hypogonadotropic hypogonadism.

  　

• Others: 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: Pituitary failure may be congenital or acquired due to 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. As 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 it is a microprolactinoma or macroprolactinoma.

    　

  • 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 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 normal. 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 normal LH levels. 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.

• Peripheral: 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. As cortisol is not secreted, a lack of feedback inhibition on the pituitary gland occurs, leading to 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 negatively 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: 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 problems may be chromosomal or nonchromosomal in nature. While chromosomal failure usually is caused by abnormalities of the sex chromosomes, autosomal disorders also are observed.

• Chromosomal: An estimated 6% 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 normal sperm density (1%). A karyotype test and a Y-chromosome test for microdeletions are indicated in patients with azoospermic or severe oligospermia (<5 million sperm per cc).

  　

• 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 47XXY karyotype and is due to a nondisjunction during the first meiotic division, two-thirds of which is of maternal origin, while mosaic forms are due to nondisjunction following fertilization. The only known risk factor is advanced maternal age. Infertility is due to 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 exam in these patients reveals gynecomastia, small testis, and eunuchoid body proportions due to delayed puberty. In some patients, secondary sex characteristics develop normally, but they usually are 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 Klinefelter patients, 20% show the presence of residual foci of spermatogenesis. While 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): XX male 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 to an autosome. Patients are often short with small firm testis and gynecomastia but have a normal sized penis. Seminiferous tubules show sclerosis.

• XYY: 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 often is 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 (46XY): Patients with Noonan syndrome, also known as male Turner syndrome, have physical characteristics similar to that of women with Turner syndrome (45X). 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 (45X/46XY): 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 often are 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, but rather require 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% of patients with oligospermia, although 7% of patients with other known causes of infertility also 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 (46XY) karyotype but are born without testis bilaterally. The male phenotype proves that androgen was present in utero. Potential causes are unknown but may be due 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 are infertile.

  　

• Down syndrome: These patients have mild testicular dysfunction with varying degrees of reduction in germ cell number. LH and FSH usually are 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.

• 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 the abnormal dilation of the veins of the pampiniform plexus of the scrotum. Varicoceles are present in 15% of the population but observed in 30-35% of primary infertile men, making it the most common surgically correctable cause of male infertility. In addition, it has been implicated as the cause of 75-85% of secondary infertility.

    　

  • Varicoceles are usually asymptomatic, but they may cause pain or testicular atrophy. Varicoceles are observed more commonly on the left side than the right. Varicoceles lead to abnormalities of both testicular spermatogenesis and steroidogenesis, and they may be associated with nearly any abnormal pattern on semen analysis patterns. Etiology of these problems is unknown, although investigators have implicated an increased intratesticular temperature, reflux of toxic metabolites, and germ cell hypoxia as potential causes of infertility.

    　

  • Indications for repair include a varicocele with infertility or a symptomatic varicocele. Much controversy exists over the issue of adolescent varicoceles and whether or not they should routinely be repaired. Many varicoceles are not associated with infertility, severe symptoms, or hypogonadism, and do not need to be fixed. After repair, 40-70% of patients have improved semen parameters, while 40% are able to achieve a pregnancy without other intervention.

• 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 one 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 normal LH and testosterone levels but have an increased FSH. 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, 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 (XRT): 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 due to 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% get orchitis, two-thirds of which is unilateral and one-third is bilateral. Orchitis develops within a few days after the onset of the parotid gland inflammation but may precede it. The virus either directly affects the seminiferous tubules or indirectly causes ischemic damage due to the intense swelling of the testicle with 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 but only one third of patients if it is bilateral.

• 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.

  　

• Others: Alcohol, cigarettes, caffeine, and marijuana may all lead to testicular failure.

  　

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

• 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 with a renal ultrasound or similar imaging tests. Patients are candidates for assisted reproduction techniques after appropriate genetic screening in the partner.

• DES exposure: An increased incidence of duct obstruction is observed in children of mothers who were exposed to DES during pregnancy.

  　

• Blockage (acquired): Genital ducts may become obstructed secondary to infections such as chlamydia, gonorrhea, tuberculosis, and smallpox. Young syndrome leads to inspissation of material in the vas deferens. Trauma, previous attempts at sperm aspiration, and inguinal surgery may result in blockage. Small calculi may block the ejaculatory ducts, or prostatic cysts may extrinsically block the ducts.

• Antisperm antibodies (ASA): ASAs 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. Due to a defect in the dynein arms, spokes, or microtubule doublet, cilia in the respiratory tract and in sperm do not function properly. Patients are troubled by sinusitis, bronchiectasis, and infertility.

• Schmidt syndrome: Schmidt syndrome is a generalized autoimmune disorder characterized by multiple primary endocrine deficiencies and circulating antibodies against the basement membrane of the testis.

• 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.

WORKUP

Lab Studies:
　

• Semen analysis: The semen analysis is the cornerstone of the male infertility workup. A specimen is collected by masturbation into a clean, dry, sterile container, or during coitus using special condoms (containing no spermicidal lubricants). The patient should be abstinent for 2-3 days prior to maximize sperm number and quality. Each day of abstinence typically is associated with an increase in semen volume of 0.4 cc and an increase in sperm density by 10-15 million sperm per cc for up to 7 days. The sample should be processed within one half to one hour, and 2 to 3 samples (at a minimum of 2-3 days apart) need to be evaluated to assess for variations in sperm number and quality. A variety of parameters are measured, such as volume, sperm density, quality, motility, and morphology. Individual tests evaluate only one aspect of a quality necessary for fertility and do not imply the ability or inability to achieve conception (see Table 1).

• Volume: Normal ejaculate volume is 1.5-5.0 cc. A small ejaculate volume may be observed in patients with retrograde ejaculation, absence of the vas deferens or seminal vesicles, ductal obstruction, hypogonadotropinism, or poor sympathetic response. An increased volume rarely is observed and is often a contaminant, such as urine.

• Semen quality: Semen is initially a coagulum that liquifies in 5-25 minutes because of prostatic enzymes. At this point, it should be able to be poured "drop by drop." Semen that is not initially a coagulum often is due to an ejaculatory duct obstruction or the absence of seminal vesicles. Nonliquification of the semen can be differentiated from benign hyperviscosity by a normal postcoital test. No excessive sperm agglutination should exist.

• Sperm density: Normal sperm density is greater than 20 million sperm per cc or at least 50-60 million total. Oligospermia is defined as less than 20 million sperm per cc, severe oligospermia is less than 5 million sperm per cc, and azoospermia is defined as no sperm present. To verify azoospermia, the semen should be centrifuged, and the pellet should be evaluated under the microscope. Also, a postejaculate urine sample should be analyzed for sperm. Truly azoospermic patients should be evaluated for ejaculatory duct obstruction by transrectal ultrasound and should undergo a hormonal evaluation, whereas oligospermia may be due to partial ejaculatory duct obstruction or anti-sperm antibodies. A decreased FSH level implies possible hypothalamic or pituitary insufficiency. Patients with testicular failure may have either high or normal FSH levels.

• Motility: Motility is described as the percent of sperm present with flagellar motion viewed on a bright-field or phase contrast microscope. Normal motility is defined as greater than 60% with normal movement. Grading is as follows: grade 0 (no movement), grade 1 (sluggish movement), grade 2 (slow movement but not straight), grade 3 (straight line), and grade 4 (terrific speed). Evaluate patients with abnormal motility for pyospermia, ASAs (anti-sperm antibodies), varicocele, sperm ultrastructural abnormalities, or partial ductal obstruction.

• Morphology

  　

  • The head, acrosome, mid piece, and tail of individual spermatozoa are analyzed by phase-contrast microscopy after fixation with Papanicolaou stain. A minimum of 200 sperm are analyzed. Normal sperm have a smooth, oval head approximately 3-5 mm long and 2-3 mm wide. More than 60% of sperm should be normal, and less than 2-3% should be immature.

    　

  • Teratospermia is defined as less than 30% normal morphology. Abnormal head shapes are described as tapered, duplicated, small, large, amorphous, and pyriform. The acrosome should be 40-70% the size of the head, and no mid piece or tail abnormalities should be present.

    　

  • Evaluate patients with a high number of immature sperm for exposure to heat, radiation, or infectious processes. These sperm show a high level of retained cytoplasmic droplets around the mid piece.

    　

  • Kruger introduced the definition of strict criteria in 1986. He objectified this test by specifically defining the normal morphological parameters, thus enhancing consistency and reproducibility among laboratory technicians. He reported a clinically significant threshold of 14% normal forms to be an excellent predictor of in vitro fertilization success. Patients with less than of 14% normal forms had a substantially reduced success rate.

• Computer-aided semen analysis (CASA): Introduced in the late 1980s, CASA uses a video camera and computer to visualize and analyze sperm concentration and movement. This semiautomated technique is thought to potentially standardize the evaluation of semen. Parameters measured include the curvilinear velocity, defined as the average distance per unit time between successive sperm positions, the straight-line velocity, the speed of forward direction, and linearity, which is the straight line/curvilinear velocity. In addition, the program measures the average path velocity, amplitude of lateral head displacement, flagellar beat frequency, and evaluates for evidence of hyperactivation. Although CASA gives good qualitative data, it is a labor-intensive procedure that includes a high initial cost and is plagued with inaccuracies when sperm concentrations are very high or very low. It has not been shown to improve patient outcomes but, rather, is very helpful for research purposes.

• Infection: An increased number of round cells often are observed in patients with infectious or inflammatory processes. While germ cells and white blood cells appear identical on microscopic examination, immunohistochemical stains are used to differentiate between the two cell types. These are performed if more than 5-10 round cells per HPF are present. An increased number of white blood cells may signify infection or inflammation of the genital tract.

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

• Anti-sperm antibody (ASA) test

• Sperm contain unique antigens that are not recognized as "self" by the body's immune system because they form after puberty. They usually are protected from the host's immune system by the blood-testis barrier.

  　

• ASAs may form when sperm are exposed to the body's defense outside of the blood-testis barrier. These antibodies bind to sperm and may lead to infertility due to a decreased ability to penetrate the cervical mucus, premature acrosome reaction, and decreased ability to bind to the zona pellucida. Known causes include ductal obstruction, infection, testicular torsion, cryptorchidism, testicular or spermatic cord trauma, or varicocele.

  　

• An estimated 60% of patients have evidence of ASAs after vasectomy, although the clinical significance has not been completely elucidated. In addition, antibodies are present in 35% of patients with CBAVD. Evidence of antibodies found in serum or seminal plasma is less prognostic than those actually bound to sperm.

  　

• ASAs should be suspected when semen analysis reveals abnormal clumping, agglutination, unexplained decreased motility, or an abnormal postcoital test.

  　

• Several methods are available to detect ASAs, such as radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA), but the most specific test is the immunobead test. In this test, rabbit ASAs are linked to polyacrylamide beads that interact with immunoglobulins attached to sperm. More than 15-20% bound is considered a positive test.

• Hormonal analysis

• Fewer than 3% of cases of male infertility are estimated to be due primarily to a hormonal cause.

  　

• A routine part of the initial evaluation is a testing of specific serum hormone levels, which usually includes FSH, LH, testosterone, and prolactin. These 4 hormones are closely related and have an impact on sperm production.

  　

• Abnormalities may be a sign of a primary hypothalamic, pituitary, or testicular problem.

• Postcoital test

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

  　

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

  　

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

• Sperm function tests: When a primary sperm defect is suspected or when other tests do not reveal the cause of infertility, perform sperm function tests to determine if a significant sperm factor exists. These analyze specific sperm functions such as the ability to undergo capacitation and the acrosome reaction, the ability to bind to the egg, and the ability to penetrate the egg. Results are important because they help guide therapy.

• Capacitation assay: This test evaluates the ability of sperm to undergo capacitation, which is necessary for fertilization. After capacitation, sperm have hyperactivated motility, which is recognized under microscopy. Those that do not undergo capacitation portend a poor response to IVF, and ICSI should be considered.

• Acrosome reaction: The acrosome reaction assay tests the ability of the sperm to undergo the acrosome reaction when exposed to inducing substances. The acrosome process, which covers the anterior two thirds of the sperm head, contains hyaluronidase and other enzymes used to digest the zona pellucida of the egg. After sperm binding and capacitation, the plasma membrane of the egg induces the acrosome to release its contents. This reaction occasionally takes place spontaneously (less than 10% of the time), although more commonly in infertile men. Under the microscope, acrosome-inducing substances are added to the sample after the sperm have undergone capacitation, which usually takes approximately 3 hours. Usually, 15-40% of the sperm undergo the acrosome reaction when stimulated and less in infertile men. The results of the test correlate with IVF success; patients with an abnormal test may need to undergo ICSI.

• Sperm penetration assay (SPA): First described in 1976 by Yanagimachi et al, the SPA checks the ability of sperm to function in vitro by evaluating capacitation, the acrosome reaction, and the ability of the sperm to fuse with the oolemma. Cross-specie fertilization usually is prevented by the zona pellucida. Hamster ova, with the zona pellucida removed, are incubated with the donor's sperm and the number of sperm penetrated per ovum is measured. A normal result is more than 5 sperm penetrations per ovus. Less than that is probably indicative of a problem. Patients with a poor SPA should proceed directly to ICSI.

  　

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

  　

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

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

Imaging Studies:
　

• Transrectal ultrasound

• A transrectal ultrasound (TRUS) is indicated in patients with azoospermia or severe oligospermia to rule out a complete or partial ejaculatory duct obstruction. TRUS also is useful to evaluate for the presence or absence of the seminal vesicles.

• A 6.5-7.5 MHz probe is used with the bladder partially filled, and the prostate, ejaculatory ducts, and seminal vesicles are evaluated. The ejaculatory ducts are normally 3-8 mm wide and 2-3 cm long.

• Obstruction is suggested by enlarged seminal vesicles, which may be due to obstructing stones, stenosis, or intraprostatic cysts. Cysts of müllerian origin are in the mid line at the utricle and contain no sperm, while those of Wolffian duct origin may be part of an ejaculatory duct diverticulum and may contain sperm.

• Those patients with ejaculatory duct obstruction are candidates for transurethral resection of the ejaculatory ducts.

• Diagnosis may be confirmed by seminal vesicle aspiration, with many sperm per high power field, indicating a probable obstruction.

• Scrotal ultrasound

• A scrotal ultrasound can be used to evaluate the anatomy of the testis, epididymis, and spermatic cord. It is useful for evaluating testicular volume and blood flow, testicular and paratesticular masses, and the presence of varicoceles.

• Investigators have debated the need to perform a testicular ultrasound on all patients with infertility because of the increased risk of testicular cancer in infertile men (1/200 vs 1/20,000 in the general population). A recent large review reported a 38% rate of abnormalities on testicular ultrasound, including 0.5% with testicular cancer and 29.7% with varicocele.

• Currently, routine screening ultrasound is not recommended or performed.

• A color flow is used to evaluate for variocele using a 7-10 MHz probe.

• Any spermatic vein greater than 3 mm or an increase in vein size with Valsalva is considered a positive test. However, Doppler ultrasound may be too sensitive of a test and may pick up subclinical varicoceles, which have not been proven to adversely affect fertility.

• Vasogram

• A vasogram is used to evaluate patency of the ductal system.

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

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

TREATMENT

Medical Care: Limited numbers of medical treatments are aimed at improving chances of conception for patients with known causes of infertility.

• Endocrinopathies

  　

  • A number of patients with hypogonadotropic hypogonadism respond to GnRH therapy or gonadotropin replacement.

    　

  • HCG is an LH analogue that may be used alone of in combination with human menopausal gonadotropin (HMG) for Leydig cell stimulation.

    　

  • Clomiphene citrate and tamoxifen are antiestrogens that block the negative feedback loop at the pituitary level, allowing a potentially increased release of gonadotropins.

    　

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

    　

  • Exogenous testosterone decreases intratesticular testosterone production, thus inhibiting Sertoli cell function and spermatogenesis.

    　

  • Treat patients with hyperprolactinemia with bromocriptine, a dopamine antagonist, or cabergoline.

• ASAs: Patients with ASA levels greater than 1:32 may respond to immunosuppression using cyclic steroids for 3-6 months. However, they must be counseled regarding the risk of avascular necrosis of the hip, weight gain, and iatrogenic Cushing syndrome.

  　

• Retrograde ejaculation

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

  　

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

  　

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

• Semen processing

  　

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

    　

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

• Lifestyle

  　

  • Encourage patients to stop smoking cigarettes and marijuana and to limit environmental exposures.

    　

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

• Infections: Treat infections with appropriate antibiotics.

Surgical Care: Experienced professionals can perform a variety of surgical interventions for the diagnosis and treatment of infertility.

MEDICATION

The goal of pharmacotherapy is to improve sperm count.
　

Drug Category: Anabolic steroids -- Testosterone replacement for primary hypogonadism, hypogonadotropic hypogonadism, and delayed puberty.

Drug Category: Estrogen receptor blockers -- Cause increased hypothalamic secretion of GnRH due to blockage of estrogen inhibition.

Drug Category: Dopamine antagonists -- Ergot derivative and dopamine receptor agonist. Acts on postsynaptic dopamine receptors, while causing no effect on other anterior pituitary functions. Mimics dopamine action of inhibition of prolactin release.

Drug Category: Menotropins -- Stimulates production of gonadal steroid hormones.

FOLLOW-UP

Prognosis:
　

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

Patient Education:
　

• Couples should be counseled that the most effective regimen is to perform coitus every 48 hours at midcycle.

MISCELLANEOUS

Medical/Legal Pitfalls:
　

• With the technological advancements in assisted reproductive techniques, a new host of ethical issues has followed.

• Gamete donation has enabled infertile couples to conceive, and many use family members as the donors to keep genetic linkages alive. However, no laws or published guidelines oversee these donations, but rather, it is left up to the individual, physician, or program. The legal battles over the rights to embryos from donated eggs or sperm, or to embryos, eggs, or sperm after divorce are still being fought.

• Technology has now proven the ability to clone animals, and the future may provide the ability to choose a child's gender and physical characteristics.

• All of these and other issues are still controversial, and it is hoped that the rate of evolution of these technologies does not exceed society's capacity to deal with the potential consequences.