For conception to occur, spermatogenesis must be normal and the seminal accessory glands must produce seminal fluids. The ducts for sperm transport must also be patent, and ejaculation must occur so the sperm can be delivered near the female’s cervix. Next, the spermatozoa must be able to travel to the uterine tubes, and they must undergo functional changes that allow them to fuse with the oolemma (plasma membrane of oocyte). Any defect in these mechanisms can result in infertility.
Infertility is defined as the inability of a couple to achieve pregnancy despite unprotected intercourse for a period of more than 12 months. About 15% of all couples are infertile, and it is estimated that a male factor plays a role in about half of the cases. In spite of this, the evaluation of the male partner is often neglected, mainly because of the high pregnancy rates that can be achieved by assisted reproductive techniques (ARTs). This practice is unfortunate because male infertility can often be cured, sparing the female partner the extensive treatment and cost of ART. Furthermore, evidence suggests that ART procedures can be associated with increased risks for both mother and child. Finally, neglecting to examine the infertile man properly risks overlooking serious conditions such as testicular cancer that may coexist with infertility.
Male infertility can be divided into pretesticular, testicular, and post-testicular forms. A comprehensive list of etiologies is presented in Table 23–3, genetic male infertility causes are listed in Table 23–4, and causes of testicular atrophy are in Table 23–5.
Table 23–3Etiology of male infertility. |Favorite Table|Download (.pdf) Table 23–3 Etiology of male infertility.
|Pretesticular ||Testicular ||Posttesticular |
Isolated LH deficiency (fertile eunuch)
Biologically inactive LH
Combined LH and FSH deficiency (eg, Kallmann syndrome)
Pituitary tumors (eg, prolactinoma)
Systemic illness (eg, cirrhosis, uremia)
Thyroid disorders (eg, hyperthyroidism, hypothyroidism)
Adrenal disorders (eg, adrenal insufficiency, congenital adrenal hyperplasia)
Drugs (eg, phenytoin, androgens)
Drugs and toxins
Medications (eg, sulfasalazine, cimetidine, nitrofurantoin, cyclophosphamide, chlorambucil, vincristine, methotrexate, procarbazine)
Ingestants (eg, alcohol, marijuana)
Environmental exposures (eg, pesticides, radiation, thermal exposure)
Chromosomal abnormalities (eg, Klinefelter syndrome [XXY seminiferous tubule dysgenesis], Y chromosome microdeletions)
Congenital absence of vas deferens, seminal vesicles
Immotile cilia syndrome
Bilateral anorchia (vanishing testes syndrome)
Leydig cell aplasia
Noonan syndrome (male Turner syndrome)
Defective androgen biosynthesis (eg, 5α-reductase deficiency)
Ductular obstruction, scarring
Pelvic, retroperitoneal, inguinal, or scrotal surgery (eg, retroperitoneal lymphadenectomy, herniorrhaphy, Y-V plasty, transurethral resection of prostate, vasectomy)
Genital tract infections (eg, venereal disease, prostatitis, tuberculosis)
Retrograde ejaculation (eg, diabetic autonomic neuropathy, postsurgical, medications)
Antibodies to sperm or seminal plasma
Penile anatomic defects (eg, hypospadias, epispadias, chordee)
Congenital absence (bilateral or unilateral) of the vas deferens; bilateral ejaculatory duct obstruction; or bilateral obstructions within the epididymides—all associated with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene
Androgen insensitivity (eg, androgen receptor deficiency, testicular feminization syndrome)
Poor coital technique
Sexual dysfunction, impotence
Table 23–4Chromosomal and genetic disorders causing male infertility. |Favorite Table|Download (.pdf) Table 23–4 Chromosomal and genetic disorders causing male infertility.
|Disorder ||Cause of Infertility ||Defect |
|Klinefelter syndrome ||Oligoazoospermia, hyalinization of seminiferous tubules || |
|XX male syndrome ||SCOS || |
|XYY male syndrome || || |
|Disorders of GnRH secretion || || |
| || || |
| || || |
| ||Decreased GnRH secretion || |
| ||Defects in G protein coupled for GnRH || |
GNRHR gene mutation
| ||Decreased GnRH secretion || |
|Disorders of androgen function || || |
| ||Excessive androgens inhibit pituitary secretion of gonadotropins || |
|Androgen insensitivity syndromes (Reifenstein syndrome, testicular feminization, Lub syndrome, Rosewater syndrome) ||Androgen insensitivity || |
|Kennedy syndrome || || |
|5α-reductase deficiency || || |
|Y chromosome microdeletions |
| || || |
| ||SCOS || |
| ||Variable phenotype: oligozoospermia to SCOS || |
| || || |
| ||Spermatogenic arrest || |
| ||Variable phenotype: oligozoospermia to SCOS || |
| || || |
| ||Variable phenotype: oligozoospermia to SCOS || |
| ||Azoospermia || |
| ||Congenital absence of vas deferens || |
Table 23–5Causes of testicular atrophy. |Favorite Table|Download (.pdf) Table 23–5 Causes of testicular atrophy.
|Testicular torsion |
|Klinefelter syndrome (47,XXY) |
|Alcoholism and cirrhosis |
|Infection (eg, mumps orchitis, gonococcal epididymitis) |
|Malnutrition and cachexia |
|Obstruction to outflow of semen |
|Drugs (eg, estrogen therapy for prostatic cancer) |
The pretesticular causes of infertility originate in either the hypothalamus (GnRH) or the pituitary (LH and FSH). These endocrinopathies are most often caused by mutations in genes involved in the biosynthesis of the hormones, growth factors or receptors, and associated signal transduction pathways. The deficiencies result in a loss of intratesticular testosterone production and cessation of spermatogenesis.
Hypogonadotropic hypogonadism is an uncommon cause of male infertility but is important to recognize because replacement therapy can be initiated. The condition is characterized either by reduced GnRH production, causing circulating levels of FSH and LH to diminish, or by rare disorders of the pituitary (with normal GnRH) that result in primary deficiencies of FSH and/or LH. These defects result in deficient androgen secretion and spermatogenesis.
Disorders resulting in abnormal synthesis and release of GnRH are most often caused by mutations, small deletions, or polymorphic expansions within genes involved in the regulation of sexual development and function. Disorders of GnRH synthesis and release can also be caused by hypothalamic tumors. Disorders without a known cause are termed idiopathic hypogonadotropic hypogonadism. Men suffering from GnRH deficiencies have firm prepubertal-sized testes and a small penis.
Kallmann syndrome refers to a syndrome of defective olfaction with hypogonadotropic hypogonadism caused by failed olfactory and GnRH axonal migration during fetal development. This is caused by a mutation in the KALIG1 gene on Xp22.3 and results in deficiency in GnRH secretion and consequent failure of pubertal initiation along with anosmia or hyposmia. In addition, patients tend to be tall and can have congenital deafness, asymmetry of the cranium and face, cleft palate, cerebellar dysfunction, cryptorchidism, or renal abnormalities. However, some Kallmann syndrome patients present only with isolated gonadotropin deficiency, manifesting as infertility.
Other causes of pubertal failure include mutations in the recently discovered hypothalamic kisspeptin peptide or its cognate receptor GPR54. With clinical implications for diagnosis and treatment of infertility and related disorders, this ligand/receptor pair has proven to be one of the key mediators of pubertal onset.
Mutations of the X-linked Dax1 gene are associated with hypogonadotropic hypogonadism and congenital adrenal hypoplasia. Dax1 is a nuclear receptor that plays a critical role in the development of the hypothalamus, pituitary, adrenal, and gonads.
GnRH receptor mutations are also associated with hypogonadotropic hypogonadism. The GnRH receptor is a G protein–coupled receptor for GnRH. Patients with GnRH mutations have a spectrum of reproductive dysfunction from partial to complete hypogonadism.
Mutations in the PC1 or convertase-1 gene are associated with hypogonadotropic hypogonadism in conjunction with obesity and diabetes mellitus. PC1 is essential in the cleavage of multiple propeptides to their active peptide hormone. The gene is believed to have a role in GnRH secretion and release.
Prader-Willi syndrome is caused either by mutations or deletions of a specific locus within paternal chromosome 15 or, less commonly, by maternal uniparental disomy (two maternal copies) of this locus. Symptoms include obesity, mild or moderate mental retardation, infantile hypotonia, and hypogonadotropic hypogonadism.
Hemochromatosis is associated with treatable hypogonadotropic hypogonadism; some men with hemochromatosis develop primary testicular failure.
Biologically inactive LH or FSH can result from genetic mutations in either the hormones or their receptors. The mutations result in a spectrum of dysfunction from complete virilization failure to less severe hypogonadism.
Pituitary mass lesions are uncommon but are recognized causes of hypogonadotropic hypogonadism and male infertility. Such lesions interfere with the release of LH and FSH, either by direct compression of the portal system or by decreasing secretion of these gonadotropins.
In hyperprolactinemia, the elevated serum prolactin level causes hypogonadism because it interferes with the normal pulsatile release of GnRH. Adenomas of the pituitary can cause hyperprolactinemia (due to infundibular compression and resultant inhibition of hypothalamic dopamine that tonically inhibits prolactin synthesis and secretion), together with headaches and visual field impairment (due to direct compression on the optic chiasm). Selective serotonin reuptake inhibitors can also cause hyperprolactinemia.
Spermatogenesis is dependent on a high androgen concentration. Genetic steroidogenic enzyme deficiencies can result in combined defects in multiple steroid hormones including testosterone and/or DHT. Androgen deficiency results in a spectrum of phenotypic abnormalities ranging from incomplete virilization to completely feminized genitalia and cryptorchid testes. Alternatively, in congenital adrenal hyperplasia, impaired corticosteroid and androgenic steroid synthesis often results in ACTH-dependent elevations in adrenal androgens (see Chapter 21).
The X-linked androgen receptor (AR) is a nuclear steroid receptor that is classically activated upon androgen binding to facilitate transcriptional activation of a host of target genes. Androgen insensitivity syndromes result from mutations in AR structure and/or function. Complete loss of AR function results in complete feminization of 46,XY individuals. Because testosterone is converted to estradiol by peripheral aromatization, estradiol levels are usually elevated and feminization occurs in a similar fashion to normal XX females at the time of puberty. In less severe cases, the phenotypic spectrum ranges from simple male infertility to ambiguous genitalia and hypospadias.
Anabolic steroid abuse results in negative feedback at the level of the hypothalamus and pituitary, and LH and FSH release is reduced. This in turn disables endogenous testosterone production and spermatogenesis because normal spermatogenesis requires both FSH and adequate intratesticular testosterone. Decreased testicular size and gynecomastia can also be seen in association with long-time anabolic steroid abuse. The extent and reversibility of these detrimental effects depend on dose and duration of use. Normal hormonal function usually returns after these agents are discontinued.
A number of conditions damage spermatogenic potential by direct effects on the testicles.
Varicoceles are considered the most common cause of subfertility in men. The term varicocele refers to abnormally dilated scrotal veins. A varicocele is present in about 15% of the normal male population, but in approximately 40% of men presenting with infertility.
Possible pathogenic mechanisms in varicocele formation include the anatomical configuration of the left internal spermatic vein, incompetent or absent valves, and potential for a partial left renal vein compression between the aorta and the superior mesenteric artery. An acute varicocele can also be caused by retroperitoneal malignancies with arteriovenous shunting into the venous system.
Varicoceles are associated with impaired spermatogenesis by one of several mechanisms: increased scrotal temperatures, alterations in testicular blood flow, reduced testicular size, overproduction of adrenal steroid metabolites, increased oxidative stress, which may damage cell membrane integrity or cause DNA damage, and alterations in the hypothalamic-pituitary-gonadal axis, leading to decreased serum testosterone levels. The pathophysiology of the impaired spermatogenesis is likely multifactorial in many cases.
Several studies have shown decreased semen quality and increased sperm DNA damage in varicocele patients compared with normal controls. However, the evidence for a clinical benefit of varicocele repair in improving fertility is controversial.
Genetic disorders are characterized as (a) abnormalities of entire chromosomes (abnormalities of the karyotype), (b) deletions of specific areas of chromosomes, or (c) specific mutations within genes. These disorders can alter spermatogenesis and impair normal development of the genital tract, thus decreasing fertilization capacity.
Chromosomal defects are categorized as either numerical or structural. Numerical chromosome abnormalities include deletion or duplication of whole chromosomes. Structural chromosome abnormalities include deletion, inversion, or duplication of a portion of a chromosome, or translocation of part of one chromosome to another chromosome. Both autosomal and sex chromosomes may be affected. Such abnormalities occur with much greater frequency in infertile men than in the general population. About 1 in 20 infertile men has a chromosomal abnormality, and most of these cases involve a sex chromosome. These men are usually azoospermic or severely oligospermic.
Klinefelter syndrome (47,XXY) is the most common chromosomal disorder associated with infertility. Patients with Klinefelter syndrome are severely oligospermic or azoospermic. The phenotype of men with Klinefelter syndrome varies but can include increased height, female hair distribution, gynecomastia, decreased level of intelligence, diabetes mellitus, obesity, increased incidence of leukemia and nonseminomatous extragonadal germ cell tumors, small firm testes, and infertility. Laboratory studies show increased serum FSH, normal or increased serum estradiol, and normal or low serum testosterone (with a tendency to decrease with age). Leydig cell function is commonly impaired in men with Klinefelter syndrome. Patients with Klinefelter syndrome who are mosaics with 46,XY/47,XXY have a less severe phenotype, with a variable sperm production.
There are other less common chromosomal defects. Most patients with mixed gonadal dysgenesis have a mosaic karyotype of 45,X/46,XY, but others have a normal 46,XY. Affected individuals can have male, female, or ambiguous genitalia, streak gonads, or normal testes. The XX male syndrome (46,XX) is caused by translocation of the SRY sex-determination gene from the paternal Y chromosome to the paternal X of the offspring, resulting in “normal” development of testes in the XX fetus, but lack of all spermatogenic genes normally found on the Y chromosome. The XYY male syndrome (47,XYY) is characterized by decreased intelligence, antisocial behavior, an increased incidence of leukemia, and impairment of spermatogenesis.
Microdeletions of the Y chromosome have been shown to be of great importance in male infertility. The long arm of the Y chromosome contains genes that are critical for spermatogenesis (Figure 23–8). The genes most often mutated in patients with defective spermatogenesis are found in the azoospermia factor region (AZF) where three nonoverlapping intervals (AZFa, AZFb, and AZFc) exist. Y chromosome microdeletions are detected by polymerase chain reaction–based mapping of molecular markers and genes. The most frequently deleted region is AZFc (~60% of Y chromosome deletions), followed by AZFb (35%) and AZFa (5%). There can also be large deletions that span more than one region.
Diagrammatic representation of areas responsible for male infertility on long arm of Y chromosome (Yq). (Redrawn, with permission, from Iammarrone E et al. Male infertility. Best Pract Res Clin Obstet Gynaecol. 2003;17:211.)
Microdeletions in the AZF region are responsible for azoospermia or severe oligozoospermia (sperm concentrations of less than 5 million/mL). Such AZF microdeletions are estimated to account for about 7–10% of male factor infertility. Affected men do not have other phenotypic abnormalities.
Among men with microdeletions in the AZFc region of the Y chromosome, 70% still have sufficient sperm production to allow sperm extraction via testis biopsy. If spermatozoa are obtained from patients with the Y deletion, they can be used for in vitro fertilization (IVF), but the deletion and infertility are transmitted to male offspring. Men with microdeletions in the AZFb and AZFa regions do not have sperm on testicular biopsy.
Cryptorchidism is the term used if testicular descent does not proceed normally during development, and the testis remains in the abdominal cavity or groin. The prevalence of cryptorchidism is approximately 3% in full-term newborns, but only 1–2% by age 6 months. About 85% of all cases of cryptorchidism are unilateral.
Failure of normal testicular descent can result in impaired spermatogenesis. About 50–70% of unilaterally cryptorchid men are oligospermic or azoospermic, and almost 100% of bilaterally cryptorchid men are azoospermic.
Exposure to toxins has also been postulated to cause defects in spermatogenesis. While numerous substances and occupations have been suspected, inadequate study sample size and confounding factors make causal relationships difficult to confirm.
The different germ cell populations display unique sensitivities to different toxins. Spermatogonia are located outside the blood-testis barrier and are exposed to any toxins in the interstitial fluid. Conversely, spermatocytes and spermatids are located inside the blood-testis barrier, which offers them some protection. Toxins that injure Sertoli cells can also impair spermatogenesis, whereas injury to the Leydig cells can reduce testosterone levels. Toxins may also interfere with hormone balance by causing alterations in androgen or gonadotropin receptor binding, alterations in circulating gonadotropin levels, and alterations in the metabolism of androgens. The effects of toxins may be reversible if the agents are removed before azoospermia occurs.
Cigarette smoking has been associated with a reduction in sperm count and motility and an increase in abnormal forms. Cigarette smoking can also cause damage to sperm DNA. A meta-analysis of 21 studies examining the effects of cigarette smoking on semen quality revealed that smoking lowered sperm concentration by 13–17% in 7 studies but had no adverse spermatogenic outcome in 14 studies. Therefore, it remains controversial whether smoking actually decreases male fertility rates.
Also controversial is whether second-hand smoke from a male partner can affect female fertility. There is, however, some evidence that maternal smoking may be related to decreased sperm counts in the male offspring. Finally, the risk of developing erectile dysfunction is almost doubled for smokers compared with nonsmokers, and this can limit male fertility.
Testicular temperatures are approximately 2°C below core body temperature, and spermatogenesis is dependent on this cooler temperature. Factors such as clothing, lifestyle, season, and fever can cause increases in scrotal temperature. Increases in scrotal temperature reduce sperm quantity and quality.
Chemotherapy and radiation therapy, used in men with testicular cancer, Hodgkin disease, or leukemia, are potent gonadotoxins. For example, both radiation therapy and chemotherapy can cause damage to the germinal epithelium, and spermatogenesis may not recover. Therefore, it is recommended that patients bank their semen before such therapy. If the semen quality is good, specimens can be preserved in aliquots large enough for intrauterine insemination. If only a single specimen is available, the sample should be divided into smaller aliquots that can be used for IVF or intracytoplasmic sperm injection.
If patients receiving chemotherapy remain azoospermic after recovery from cancer, there is still a significant chance (41% in one study) that sperm can be obtained with testicular sperm extraction for IVF or intracytoplasmic sperm injection.
Testicular or epididymal infections may lead to infertility. For example, although mumps is generally a self-limited disease in children, mumps may result in orchitis in postpubertal males. Necrosis from acute swelling and increased intratesticular pressure can cause permanent testicular atrophy and infertility.
Epididymitis can lead to scarring of the tubules and obstruction of sperm flow (discussed below). In the absence of ductal obstruction, however, the role of infection in causing infertility is controversial. Potential deleterious effects of infection on male fertility include decreases in spermatogenesis, breaches in the blood-testis barrier leading to sperm autoimmunity, and seminal oxidative stresses due to an increase in seminal fluid oxidant levels or a decrease in seminal fluid antioxidant levels.
Torsion of the spermatic cord with interruption of testicular blood flow results in acute, intense testicular pain. If untreated, the absence of blood flow after 4–6 hours of torsion causes irreparable damage. Torsion may also induce sperm autoimmunity due to a breakdown of the blood-testis barrier during the ischemic event.
Testicular trauma can lead to scrotal or testicular edema, hematoma, hematocele, hydrocele, torsion, fracture, or rupture. These may result in testicular atrophy as well as the development of antisperm antibodies. In both testicular rupture and torsion, early surgery is needed to ensure testicular salvage. The ruptured testicle can be restored in up to 90% of patients if the rupture is treated within 72 hours, but torsion of the testicle must be treated within 6 hours to obtain a similar result.
Ductal obstruction can occur anywhere along the male reproductive system, and results of semen analysis vary with the site of obstruction. Complete obstruction of the ejaculatory duct results in a low-volume, acidic, fructose-negative ejaculate. Obstruction of the vasa or epididymides results in a normal-volume, alkaline, fructose-positive ejaculate. Men with ductal obstruction as the only cause for their infertility have normal serum testosterone and FSH levels.
Obstruction is either congenital or acquired. Congenital causes include congenital atresia or stenosis of the ejaculatory ducts as well as utricular or müllerian and wolffian duct cysts. Acquired vasal obstruction may be caused by inguinal or pelvic surgery but is most commonly the result of a vasectomy. Epididymal obstruction may be caused by scrotal surgery and epididymitis. Epididymitis is inflammation most commonly due to a urinary tract infection. In men younger than 35 years, the most common pathogens are the sexually transmitted organisms Chlamydia trachomatis and Neisseria gonorrhoeae. In young children and older men, the most common pathogen is Escherichia coli. Epididymitis in a child mandates exclusion of a urinary tract anomaly.
Finally, ejaculatory duct obstruction may be due to genitourinary infections, pelvic surgery, urethral trauma, chronic prostatitis, and calcifications and cysts in the prostate or seminal vesicles.
Congenital bilateral absence of the vas deferens (CBAVD) is part of the phenotypic spectrum of cystic fibrosis (CF). CF is an autosomal recessive disease, and about 1 in 25 Caucasians are heterozygous carriers. Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the disease; more than 500 such mutations have been identified. CBAVD occurs in 1–2% of infertile men, making it the most common congenital abnormality of the wolffian duct system. Although most patients with classic CF carry severe mutations on both CFTR gene loci, patients with CBAVD can have a severe mutation in only one CFTR gene coupled with a minor mutation in the other or minor mutations on both loci. Men with CBAVD also have hypoplastic, nonfunctional seminal vesicles and ejaculatory ducts, as well as epididymal remnants that are frequently composed of only the caput regions that are firm and distended. Other manifestations of the disease of CF such as pulmonary, pancreatic, and gastrointestinal dysfunction are usually absent.
However, spermatogenesis is not impaired in these patients, and they can undergo sperm-retrieval procedures and have their semen used in ART. To diminish the possibility of transmitting CF to the offspring, men with CBAVD and their wives should be referred to genetic counseling and screened for CFTR mutations before sperm retrieval and IVF.
Men with idiopathic epididymal obstruction have also been found to have an increased incidence of CF mutations and probably simply represent a variant phenotype from the patient with classic CBAVD. These men should also undergo CF testing before epididymal sperm aspiration or reconstructive surgery. Finally, patients presenting with unilateral absence of the vas deferens are also at risk of mutations and should undergo analysis of the CFTR gene.
Ejaculatory duct obstruction is an uncommon cause of male infertility, representing about 1% of cases. Most cases are bilateral because of the close proximity of the ostia of both ejaculatory ducts. The condition may be congenital or acquired. Occasionally, congenital isolated ejaculatory duct obstruction may be associated with CFTR mutations, and genetic screening is appropriate. Acquired cases may be due to prostatic nodule formation or inspissated secretions in the ejaculatory ducts causing calculi. Utricular cysts may also obstruct the ejaculatory ducts.
Symptoms from ejaculatory duct obstruction include infertility, decreased ejaculate volume, reduced ejaculatory force, hematospermia, pain with ejaculation, and dysuria. The physical examination of patients with ejaculatory duct obstruction is usually normal. However, some may have a palpable seminal vesicle or mass on rectal examination, or prostatic or epididymal tenderness.
Clinically, ejaculatory duct obstruction must be considered in patients with azoospermia, low ejaculate volume, absence of fructose in the ejaculate, and normal hormone profiles. Transrectal ultrasonography (TRUS) has led to the identification of patients with seminal vesicle dilation or genitourinary cysts causing reduced ejaculatory volume with oligospermia or azoospermia.
Partial obstruction of the ejaculatory duct has also been recognized. Affected patients have low-volume ejaculate and variable semen quality. Unfortunately, semen quality may worsen after attempting corrective surgery. Seminal vesicle aspiration after ejaculation may aid in diagnosing partial ejaculatory duct obstruction.
Immunologic infertility may result from a breach in the blood-testis barrier, exposing the mature spermatozoa to the immune system with the formation of antisperm antibodies. These antibodies may be present in the blood or in seminal fluids. Risk factors for the formation of antisperm antibodies include trauma to the testes, epididymitis, congenital absence of the vas deferens, and vasectomy. It may also be caused by dysregulation of normal immunosuppressive activities within the male reproductive tract. Antisperm antibodies are found in 5–10% of infertile couples but are also present in 1–3% of fertile men. Antisperm antibodies react with all of the major regions of sperm and can impair sperm motility, sperm penetration through the cervical mucus, acrosome reaction, and sperm-oocyte interactions and fertilization.
High levels of circulating antisperm antibodies may reduce successful outcomes from treatment by intercourse, intrauterine insemination, or IVF. However, if intracytoplasmic sperm injection is used in conjunction with IVF, antisperm antibodies do not have a negative effect on the outcome of the procedure.
Disorders of ejaculation are uncommon but important causes of male infertility. The disorders can be divided into premature ejaculation, anejaculation, and retrograde ejaculation.
Premature ejaculation is the inability to control ejaculation for a satisfactory length of time during intercourse. The condition has been reported to affect up to 31% of men 18–59 years of age. Premature ejaculation causes distress as a sexual dysfunction for both partners but seldom leads to infertility, as ejaculation usually occurs intravaginally.
Anejaculation describes the complete absence of seminal emission into the posterior urethra. True anejaculation is always connected with central or peripheral nervous system dysfunction or with drugs. Orgasm (climax) may or may not be achieved. Spinal cord injury is the most common neurological cause of anejaculation, even though many men with spinal cord injury do have reflex erections and some capability for vaginal intercourse. Congenital spinal abnormalities, such as spina bifida, and other neurological conditions that affect spinal cord function or its sympathetic outflow (multiple sclerosis, transverse myelitis, and vascular spine injuries) can also impair ejaculation. These disorders resemble the spinal cord injury group in their dysfunction. Periaortic or pelvic surgery, including retroperitoneal lymph node dissection, can damage the nerves and cause ejaculatory dysfunction. Finally, men with diabetes mellitus are at risk for neuropathy, which can affect ejaculatory function. Typically, men with diabetic neuropathy develop ejaculatory dysfunction in a slowly progressive fashion, going from a decreased amount of ejaculate to retrograde ejaculation to anejaculation. As with other long-term complications of diabetes, this condition is related to poor control of the patient’s blood sugar. Several classes of drugs are also potentially responsible for anejaculation: α-adrenergic blockers, antipsychotics, and antidepressants. Anejaculation can also be psychogenic or idiopathic.
Retrograde ejaculation accounts for 0.3–2% of cases of male infertility. It is caused by a dysfunction in bladder neck closure that results in a total or partial absence of antegrade ejaculation. In this condition, with ejaculation, the ejaculate flows into the bladder, the path of least resistance. Because bladder neck closure is controlled by α-adrenergic neurons of the sympathetic nervous system, the condition can be caused by the same conditions as neurogenic anejaculation: retroperitoneal lymph node dissection, diabetes mellitus, Y-V plasty and other bladder neck surgery, transurethral resection of the prostate (TURP), and idiopathic. Drug causes included α1-adrenoreceptor antagonists, antipsychotics, and antidepressants.
Retrograde ejaculation is diagnosed when, after absent or intermittent emission of ejaculate during ejaculation, sperm is found in the bladder urine, which may be cloudy. Patients experience a normal or decreased orgasm but may note a “dry” ejaculation.
While there are genetic causes of male infertility, in many instances the infertility is classified as idiopathic (discussed later). Despite advances in molecular diagnostics, the pathophysiology of spermatogenic failure in a majority of infertile men remains unknown. ARTs are the best treatment option for patients with idiopathic oligospermia.
Percutaneous or open testicular biopsy specimens may show any of several lesions involving the entire testes or only portions. The most common lesion is “maturation arrest,” defined as failure to complete spermatogenesis beyond a particular stage. There can be early or late-arrest patterns, with cessation of development at either the primary spermatocyte or the spermatogonial stage of the spermatogenic cycle. The second most common and least severe lesion is “hypospermatogenesis,” in which all stages of spermatogenesis are present but there is a reduction in the number of germinal epithelial cells per seminiferous tubule. Peritubular fibrosis may be present. “Germ cell aplasia” is a more severe lesion characterized by complete absence of germ cells, with only Sertoli cells lining the seminiferous tubules (Sertoli cell–only syndrome [SCOS]). The most severe lesion (eg, in Klinefelter syndrome) is hyalinization, fibrosis, and sclerosis of the tubules. These findings usually indicate irreversible damage.
What are the major categories of causes of male infertility? Name several specific causes in each category.
From the perspective of the male reproductive system, what are the steps that must occur for conception?
What is the value of testing for a CFTR mutation or Y chromosome microdeletion?
What is the most common cause of obstructive azoospermia in the population?
A couple should undergo an evaluation for infertility if pregnancy fails to occur within one year of regular unprotected intercourse. Evaluation should be done before one year if there are risk factors for infertility either in the male or in the female or if the couple is worried about infertility. Also, an evaluation can be initiated sooner if the couple has a good understanding of ovulation timing, and they have had more than simple random attempts at pregnancy. The reason for initiating an examination sooner rather than later is that the longer a couple remains infertile, the less likely that treatment will work.
The evaluation should attempt to identify an underlying cause of the infertility in order to either initiate treatment or ART or to recommend donor insemination or adoption. The evaluation should also identify underlying pathology that requires medical attention. If the patient is to undergo ART, a genetic evaluation of the infertile man is important in order to avoid transferring possible abnormalities to the child.
The full evaluation of the infertile man should consist of a history, physical examination, and laboratory tests, including both semen analysis and endocrine evaluation.
A complete general medical history and a comprehensive reproductive history are required.
With regards to the reproductive history, the duration of infertility and information on coital technique, frequency, and timing are assessed. Because sperm survival in the female reproductive tract is about 2–5 days, the most effective time of intercourse is in the 48 hours after the ovulation. Pregnancy rates are highest with daily intercourse around this time. The history should inquire about use of lubricants since many of these are spermicidal. The patient is also asked about general sexual function including erectile and ejaculatory function.
The general medical history must also include developmental history, including congenital abnormalities, childhood illnesses, and pubertal development. Treatment for delayed puberty is obviously salient.
Information on systemic medical illnesses, prior surgeries or traumas, and genitourinary infections should be noted. Respiratory problems are especially important, as there is a correlation between sinopulmonary conditions and infertility.
Past surgeries may have an impact on fertility. Any pelvic surgery can interrupt the vas deferens or cause neurogenic erectile or ejaculatory dysfunction. Retroperitoneal surgery can impair seminal emission due to injury to the sympathetic nervous system. Hernia repair can cause an iatrogenic injury to the vas deferens.
Current, as well as past, medications should be listed. Of particular interest are antihypertensive agents (particularly alpha blockers), antidepressants, and anabolic steroids such as testosterone and others contained in dietary supplements. Possible gonadotoxin exposure must be assessed. The patient should be asked specific questions regarding cigarette smoking, marijuana use, and excessive alcohol intake, which can all suppress spermatogenesis. The family history should include questions regarding reproduction, hypogonadism, cryptorchidism, congenital defects, and cystic fibrosis.
The physical examination should include a general evaluation, but it should also focus on the secondary sex characteristics and genitalia.
Androgen status is evaluated by assessing the secondary sex characteristics, including body habitus, virilization, body hair, and gynecomastia. The penis should be examined to look for the location of the urethral meatus and penile curvature.
Examination of the genitalia is performed by palpation of the testes with the patient standing. Testicular size is measured by means of calipers, orchidometer, or ultrasound. The normal adult testis is ovoid, measuring 4–5 cm in length and 2–3 cm in both transverse and anteroposterior dimensions and has a mean volume of at least 20 mL. Small testes most likely indicate impaired spermatogenesis since the seminiferous tubules form over 90% of the testis. Abnormal testicular dimensions are present in about two-thirds of men with infertility. In men with severe spermatogenic defects, such as those with Klinefelter syndrome or Y chromosome microdeletions, the testicular size is that of a prepubertal male.
The examination should also identify the presence of scrotal pathology including hydroceles, spermatoceles, varicoceles, and hernias. The vas deferens and epididymis should be examined for obstruction, manifested by induration and enlargement of these structures. Physical examination may reveal absence of the vas deferens and epididymis. In such patients, renal ultrasound should be performed because vasal agenesis can be associated with renal anomalies.
Varicocele examination should be done in a warm room to allow for complete relaxation of the scrotal wall. The patient needs to be examined standing, at rest, and again with Valsalva maneuver. Approximately 90% of varicoceles are left sided. Varicoceles are graded from 1 to 3. With the patient standing, a grade 3 varicocele is readily visible; a grade 2 varicocele is palpable without employing the Valsalva maneuver; and a grade 1 varicocele is palpable only with the Valsalva maneuver. The patient should also be examined in the lying position, to ensure that the dilated veins collapse. If they remain dilated after assuming the recumbent position, there is a higher likelihood of retroperitoneal pathology as the source of the varicocele, and an imaging study is indicated. Also, a large difference in spermatic cord diameter between standing and recumbent positions may be an indication that a varicocele is present.
Semen collection should be done by masturbation into a glass container because plastic may contain spermatocidal chemicals. Standard instructions for semen collection include abstinence of 2–3 days. Longer periods of abstinence lead to decreased sperm motility, and shorter periods result in low semen volume and sperm concentration.
Semen analysis provides information on semen volume and sperm concentration, motility, and morphology. This information helps to define the severity of the male factor in infertility in a couple. Semen analysis also includes examination of the spermatozoa and the seminal fluid. In normal men, the ejaculate volume is ≥1.5 mL or more, and the normal semen pH is slightly alkaline (≥7.2). According to the latest standards of the World Health Organization, normal sperm parameters include sperm concentration ≥15 million sperm/mL, progressive motility ≥32% motile sperm, and normal morphology ≥44%. Sperm motility is defined as the percentage of sperm moving in 10 random high-power fields. Sperm morphology is evaluated by Kruger Criteria, which divides sperm into normal and abnormal morphology on the basis of a normal range of more than 4%. Standard semen analysis criteria are shown in Table 23–6.
Table 23–6Semen analysis: normal values and definitions. |Favorite Table|Download (.pdf) Table 23–6 Semen analysis: normal values and definitions.
|Characteristic ||Reference Standard |
|Ejaculate volume ||>1.5 mL |
|pH ||≥7.2 |
|Sperm concentration ||≥15 million/mL |
|Sperm count ||≥39 million/mL |
|Sperm motility ||≥40% total motility and 32% with progressive motility |
|Sperm morphology ||≥4%1 with normal forms |
|Term ||Definition |
|Normospermia ||Normal ejaculate (as defined by reference standards above) |
|Oligozoospermia ||Sperm concentration <15 million/mL |
|Asthenozoospermia ||<32% of spermatozoa with progressive motility |
|Azoospermia ||No spermatozoa in ejaculate |
|Aspermia ||No ejaculate |
A semen analysis can diagnose 9 out of 10 men with reduced semen quality. However, because semen quality varies over time and is often affected by exogenous factors, a single semen analysis has a low specificity. Therefore, two to three tests at least one month apart are recommended.
If sperm are completely absent on semen analysis, the specimen should be centrifuged to assess for very low sperm numbers. The finding of any sperm rules out complete ductal obstruction or complete absence of spermatogenesis. If persistent low volume is seen, examination of the post-orgasm urine should be undertaken to exclude retrograde ejaculation.
Evidence of sperm agglutination should be noted; increased clumping is suggestive of inflammatory or immunologic processes. Testing for antisperm antibodies would be indicated in such cases.
About 25% of men with sperm concentrations below 12.5 million/mL can father a child through spontaneous conception; conversely, 10% of men are infertile despite a sperm concentration of up to 25 million/mL. This indicates that some men may have dysfunctional sperm despite normal semen parameters. In other words, the normal ranges for the semen analysis provide an indication of a man’s fertility, but its values are not absolute. In such men, a number of specialized tests can be used to assess the reason for infertility.
Additional tests of the ejaculate can also be important. Absent or low-volume ejaculate suggests retrograde ejaculation, lack of emission, ejaculatory duct obstruction, hypogonadism, or CBAVD. With low semen volumes (<1 mL) and azoospermia, the seminal pH and fructose content should be determined. If both are low, it suggests agenesis, decreased function, or obstruction of the seminal vesicles.
Patients with partial ejaculatory duct obstruction often present with low-volume semen, oligoasthenospermia, and poor forward progression of sperm (see the section on post-testicular causes).
An endocrine evaluation of the hypothalamic-pituitary-testicular axis should be performed if sperm concentration is reduced. Spermatogenesis is evaluated by serum FSH and inhibin, while the Leydig cell function is evaluated by serum LH, testosterone, sex hormone–binding globulin (SHBG), and free or bioavailable testosterone. A single measurement is usually sufficient to determine a patient’s clinical endocrine status. The relative values of testosterone, LH, FSH, and prolactin can often identify the cause of the reduced semen parameters.
Men without sperm production produce very low levels of inhibin, leading to high FSH levels. Conversely, normal FSH and inhibin levels in an azoospermic man suggest normal spermatogenesis with obstruction. In men with spermatogenic arrest, normal values of FSH and inhibin can be found, especially if maturation arrest is present, since there may be enough spermatogenic progress to allow inhibin secretion. A combination of both inhibin and FSH levels has been shown to have a better diagnostic value than either one alone.
Low or nonmeasurable FSH and LH levels are found in patients with pituitary or hypothalamic hypogonadism and in patients with human chorionic gonadotropin (hCG)–producing testicular tumors. Such levels are also seen in patients with a history of anabolic steroid abuse. Notably, these synthetic substances are not measurable by standard testosterone assays.
Combined elevation of FSH and LH levels reflects a decline in both Sertoli cell and Leydig cell function caused by direct testicular damage.
Men with hypogonadotropic hypogonadism should undergo magnetic resonance imaging (MRI) of the pituitary gland and the hypothalamus to evaluate the possibility of a pituitary tumor. If the serum gonadotropin levels are low and the serum testosterone level is half the lower limit of normal, further evaluation of the remaining pituitary hormones should also be performed. This includes assessment of other pituitary–end-organ axes, to exclude panhypopituitarism. The thyroid axis is most commonly checked by obtaining serum thyroid-stimulating hormone (TSH) and free T4 levels. Serum prolactin should be measured to exclude a prolactin-secreting adenoma. Finally, if the hypogonadotropic hypogonadism remains unexplained, serum iron, total iron-binding capacity, and ferritin levels should be obtained to exclude hemochromatosis.
Fructose is produced in the seminal vesicles, and its absence in the semen implies obstruction of the ejaculatory ducts. This test is currently used sparingly, as more emphasis is placed on low semen volume as a screening test and transrectal ultrasound of the prostate as a confirmatory test. Obstruction of the ejaculatory ducts is strongly suggested by a seminal vesicle anteroposterior diameter of 1.5 cm or more on ultrasound.
Leukospermia (excessive numbers of leukocytes in the semen) may adversely affect sperm movement and fertilization ability, perhaps because of excessive generation of reactive oxygen species by the leukocytes. Also, with active prostatic infection, swelling of the prostate can lead to a functional obstruction of the ejaculatory ducts. The finding of leukospermia should prompt further investigations to exclude a genital tract infection.
A variety of in vitro tests have been developed to assess sperm function in an attempt to explain previously hidden male factors in couples with unexplained infertility. These couples have significantly lower IVF rates compared with those in whom simple uterine tubal problems can be identified. These tests are designed to uncover defects in sperm capacitation and motion, in binding to the zona pellucida, in acrosome reaction, and in ability to penetrate the oocyte. The in vitro sperm mucus-penetration test assesses the capacity of spermatozoa to move through a column of midcycle cervical mucus and aids in detection of impaired motility caused by antibodies.
In the optimized sperm mucus-penetration test, the infertile man’s sperm are placed in egg yolk buffer, cooled, and stored at cold temperature overnight and then are subjected to rapid heating in the morning and are incubated with hamster oocytes that have had the zona pellucida removed enzymatically to allow penetration. Results are reported as either the percentage of ova that have been penetrated (normal is 100% of the oocytes penetrated) or as the number of sperm penetrations per ovum, termed the sperm capacitation index (normal is >5).
The hemizona assay assesses the fertilizing capability of sperm using the zona pellucida from a nonfertilizable, nonliving human oocyte. The zona is divided in half. One half is incubated with the infertile man’s sperm, and the other half is incubated with sperm from a known fertile donor. The number of sperm binding to the zona is compared and expressed as a ratio. However, a major problem with this assay is the limited availability of human ova. The identification of zona pellucida glycoprotein 3 (ZP3) as the primary determinant of sperm-zona binding has led to exploration of the use of recombinant human ZP3 rather than the zona itself for testing sperm-zona interactions.
High-resolution transrectal ultrasound can be used to evaluate the seminal vesicles for dysplasia or obstruction; the ejaculatory ducts for scarring, cysts, or calcifications; and the prostate for calcifications.
Internal spermatic venography is occasionally used to demonstrate testicular venous reflux in a man with a suspected varicocele when the physical examination is difficult or in a man with a suspected recurrence after surgical repair.
Testicular biopsy is useful in azoospermic men to distinguish intrinsic testicular abnormalities from ductal obstruction. Testicular biopsy can recover some spermatozoa for intracytoplasmic sperm injection in nearly all men with azoospermia due to obstruction and in 40–75% of men with nonobstructive azoospermia, depending on the reason for the poor production. The best yield of operative sperm retrieval is in men with hypospermatogenesis, followed by those with germinal aplasia (due to presence of patchy normal sperm production). The prognosis is worst in men with maturation arrest, in whom a probable genetic “block” of advanced sperm production is a likely cause.
A suggested algorithm for the evaluation and treatment of male infertility is shown in Figure 23–9.
Approach to diagnosis of male infertility. ART, assisted reproductive technologies; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone; PRL, prolactin. (Redrawn, with permission, from Gardner DG et al. Greenspan’s Basic and Clinical Endocrinology, 9th ed. McGraw Hill, 2011.)
Benign Prostatic Hyperplasia
Benign prostatic hyperplasia is nonmalignant growth of the prostate stroma and epithelial glands that causes enlargement of the prostate gland. Growing slowly over decades, the gland can eventually reach up to 10 times the normal adult prostate size in severe cases. Benign prostatic hyperplasia is a common age-related disorder. Most men are asymptomatic, but clinical symptoms and signs occur in up to one-third of men older than 65 years, and each year more than 500,000 men in the United States undergo TURP.
The cause of benign prostatic hyperplasia is unknown. However, aging and hormonal factors are both clearly important. Age-related increases in prostate size are evident at autopsy, and the development of symptoms is age-related. Data from autopsy studies show pathologic evidence of benign prostatic hyperplasia in less than 10% of men in their 30s, in 40% of men in their 50s, in more than 70% of men in their 60s, and in almost 90% of men in their 80s. Clinical symptoms of bladder outlet obstruction are seldom found in men younger than 40 years but are found in about one-third of men older than 65 years and in up to three-fourths of men at age 80 years. Prostatic androgen levels, particularly DHT levels, play an important role in development of the disorder. These factors are discussed below.
The normal prostate is composed of both stromal (smooth muscle) and epithelial (glandular) elements. Growth of each of these elements—alone or in combination—can result in hyperplastic nodules and ultimately the symptoms of benign prostatic hyperplasia. Pathologically, the hyperplastic gland is enlarged, with a firm, rubbery consistency. Although small nodules are often present throughout the gland, benign prostatic hyperplasia arises most commonly in the periurethral and transition zones of the gland (Figure 23–10). With advancing age, there is an increase in the overall size of the transition zone as well as an increase in the number—and later the size—of nodules. The urethra is compressed and has a slit-like appearance.
Structure of the prostate. (Redrawn, with permission, from Chandrasoma P et al. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.)
Histologically, benign prostatic hyperplasia is a true hyperplastic process with an increase in prostatic cell number. The prostatic nodules are composed of both hyperplastic glands and hyperplastic stromal muscle. Most periurethral nodules are stromal in character, but transition zone nodules are most often glandular tissue. The glands become larger than normal, with stromal muscle between the proliferative glands. Perhaps as much as 40% of the hyperplastic prostate is smooth muscle. The cellular proliferation leads to a tight packing of glands within a given area. There is an increase in the height of the lining epithelium, and the epithelium often shows papillary projections (Figure 23–11). There is also some hypertrophy of individual epithelial cells.
Benign prostatic hyperplasia. (Reproduced, with permission, from Chandrasoma P et al. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.)
In men with benign prostatic hyperplasia, the bladder can show both detrusor (bladder wall) smooth muscle hypertrophy and trabeculation associated with an increase in collagen deposition. This is due to the increased bladder pressure created by obstruction of the urinary system.
Although the actual cause of benign prostatic hyperplasia is undefined, several factors are known to be involved in the pathogenesis. These include age-related prostatic growth, prostatic capsule, androgenic hormones and their receptors, prostatic smooth muscle and adrenergic receptors, stromal-epithelial interactions and growth factors, and detrusor responses.
Age-Related Prostatic Growth
The size of the prostate does not always correlate with the degree of obstruction. The amount of periurethral and transition zone tissue may relate more to the degree of obstruction than the overall prostate size. However, the idea that the clinical symptoms of benign prostatic hyperplasia are due simply to a mass-related increase in urethral resistance is probably too simplistic. Instead, some of its symptoms may be due to obstruction-induced detrusor dysfunction and neural alterations in the bladder and prostate. This has been demonstrated in men with lower urinary tract symptoms undergoing urodynamic testing, which measures perfusion pressure of the urethra.
The presence of a capsule around the prostate is thought to play a role in development of obstructive symptoms. Besides man, the dog is the only animal known to develop benign prostatic hyperplasia. However, the canine prostate lacks a capsule, and dogs do not develop obstructive symptoms. In men, the capsule presumably causes the “pressure” created by the expanded periurethral-transition zone tissue to be transmitted to the urethra, leading to an increase in urethral resistance. Surgical incision of the prostatic capsule or removal of the obstructing portion of the prostate, whether by transurethral resection or by open prostatectomy, is effective in relieving symptoms.
Hormonal Regulation of Prostatic Growth
Development of benign prostatic hyperplasia requires testicular androgens as well as aging. There are several lines of evidence for this relationship. First, men who are castrated before puberty or who have disorders of impaired androgen production or action do not develop benign prostatic hyperplasia. Second, the prostate, unlike other androgen-dependent organs, maintains its ability to respond to androgens throughout life. Androgens are required for normal cell proliferation and differentiation in the prostate. They may also actively inhibit cell turnover and death. Finally, androgen deprivation at various levels of the hypothalamic-pituitary-testicular axis can reduce prostate size and improve obstructive symptoms (Table 23–7).
Table 23–7Mechanisms and side effects of antiandrogenic treatment for benign prostatic hyperplasia. |Favorite Table|Download (.pdf) Table 23–7 Mechanisms and side effects of antiandrogenic treatment for benign prostatic hyperplasia.
|Agent ||Mechanism ||Side Effects1 |
|Androgen ablation |
|GnRH agonists (eg, nafarelin, leuprolide, buserelin, goserelin) ||Inhibits pituitary LH secretion, decreases T and DHT. Reduces prostate volume by ≈35%. ||Hot flushes, loss of libido, impotence, gynecomastia. |
|Abiraterone ||Inhibitor of cytochrome P450. || |
|True antiandrogens |
|(eg, flutamide, bicalutamide) ||Androgen receptor inhibition. ||Gynecomastia or nipple tenderness, no significant incidence of impotence. |
|5α-Reductase inhibitors2 |
|(eg, finasteride, dutasteride) ||Decreases DHT, no alteration in T or LH. Reduces prostate volume by ≈20%. ||3–4% incidence of impotence and decreased libido. |
|Mixed mechanism of action |
|Progestins (eg, megestrol acetate, hydroxyprogesterone caproate, medrogestone) ||Inhibits pituitary LH secretion, decreases T and DHT, androgen receptor inhibition. ||Loss of libido, impotence, heat intolerance. |
|Cyproterone acetate ||Androgen receptor inhibition, inhibits pituitary LH secretion, variable decreases in T and DHT. ||Loss of libido, impotence (variable). |
Although androgenic hormones are clearly required for the development of benign prostatic hyperplasia, testosterone is not the primary androgen that acts on the prostate. Instead, 80–90% of prostatic testosterone is converted to the more active metabolite DHT by the enzyme 5α-reductase. Two subtypes of 5α-reductase (type 1 and type 2) have been described. Both type 1 and type 2 isoenzymes are found in skin and liver, but only the type 2 isoenzyme is found in the fetal and adult urogenital tract, including both basal epithelial cells and stromal cells in the prostate. Two 5α-reductase inhibitor drugs are used clinically: Finasteride inhibits only the type 2 isoenzyme, and dutasteride inhibits both the type 1 and 2 isoenzymes (see later). In the prostate, it appears that DHT synthesis largely depends on the type 2 enzyme and that, once it is synthesized, the DHT acts in a paracrine fashion on androgen-dependent epithelial cells. The nuclei of these cells contain large numbers of androgen receptors (Figure 23–12). DHT levels are the same in hyperplastic and normal glands. However, prostatic levels of DHT remain high with aging even though peripheral levels of testosterone decrease. These decreases in plasma androgen levels are further amplified by an age-related increase in the plasma SHBG level, resulting in relatively greater decreases in free testosterone than in total testosterone levels.
Mechanism of androgen action on prostatic stromal and epithelial cells. After testosterone (T) diffuses into the cell, it can interact directly with the androgen (steroid) receptors bound to the promoter region of androgen-related genes. In the stromal cell, a majority of T is converted into dihydrotestosterone (DHT), which acts in an autocrine fashion in the stromal cell and in a paracrine fashion after diffusing into nearby epithelial cells. DHT produced peripherally in skin and liver can also diffuse into the prostate and act in an endocrine fashion. *5α-Reductase: steroid-5α-reductase, α polypeptide 2 (3-oxo-5α -steroid Δ4-dehydrogenase α) or SRD5A.
Suppression of androgens leads to reduction in prostate size and relief of symptoms of bladder outlet obstruction. True anti-androgens, which block the action of testosterone and DHT in the prostate, should be distinguished from agents that impair androgen production (Table 23–7). GnRH agonists work by paradoxically downregulating GnRH receptors in the pituitary, producing a transient increase and subsequent long-term reduction in concentrations of LH. A variety of antiandrogen treatment approaches have been used clinically, including GnRH agonists (nafarelin, leuprolide, buserelin), androgen receptor inhibitors (cyproterone acetate, flutamide), progestogens, and 5α-reductase inhibitors (finasteride, dutasteride) (Figure 23–13). Complete suppression of androgen action can lead to intolerable adverse effects, such as erectile dysfunction, flushing, and loss of libido. However, the 5α-reductase inhibitors finasteride and dutasteride suppress both plasma and prostatic DHT levels by approximately 65–95%. Treatment with these agents has been shown to induce significant decreases in the size of the prostate as a whole and in the size of the periurethral zone. The 5α-reductase inhibitors must be given for at least 6–12 months to have beneficial effects and must be continued indefinitely thereafter. Both GnRH agonists and 5α-reductase inhibitors have been shown to be effective in improving symptoms and urinary flow rates in patients with benign prostatic hyperplasia, particularly in men with larger (>40 g) prostates. The 5α-reductase inhibitors are less effective than GnRH agonists in reducing the size of the prostate but cause fewer side effects. Because of the adverse side effects produced by total androgen deprivation with GnRH agonists, and because the 5α-reductase inhibitors are effective without these side effects, GnRH agonists are not used in the everyday treatment of symptoms from benign prostatic hyperplasia.
Site of action of antiandrogens and 5α-reductase inhibitors. X, site of blockade. *5α-Reductase: steroid-5α-reductase, α polypeptide 2 (3-oxo-5α-steroid Δ4-dehydrogenase α) or SRD5A. (Redrawn, with permission, from Oesterling JE. Endocrine therapies for symptomatic benign prostatic hyperplasia. Urology. 1994 Feb;43[2 suppl]:7–16.)
Androgen receptor levels remain high with aging, thus maintaining the mechanism for androgen-dependent cell growth. Nuclear androgen receptor levels have been found to be higher in prostatic tissue from men with benign prostatic hyperplasia than in that from normal controls. The regulation of androgen receptor expression in benign prostatic hyperplasia is now being studied at the transcriptional level.
Finally, androgens are not the only important hormones contributing to the development of benign prostatic hyperplasia. Estrogens appear to be involved in induction of the androgen receptor. Serum estrogen levels increase in men with age, absolutely or relative to testosterone levels. Age-related increases in estrogens may thus increase androgen receptor expression in the prostate, leading to increases in cell growth (or decreases in cell death). Intraprostatic levels of estrogen are increased in men with benign prostatic hyperplasia. Patients with benign prostatic hyperplasia who have larger prostatic volumes tend to have higher plasma levels of estradiol. Studies of prostatic specimen tissue have documented an accumulation of DHT, estradiol, and estrone that correlates with patient age. The results show a dramatic increase of the estrogen-androgen ratio with increasing age, particularly in the stroma of prostatic tissue.
Investigations have demonstrated powerful cell-specific, nontranscriptional effects of estradiol on the human prostate. Estradiol, acting in concert with SHBG, has been found to produce an eightfold increase in intracellular cAMP in hyperplastic prostatic tissue. This increase in cAMP does not occur with estrogens such as diethylstilbestrol, which do not bind to SHBG, and is not blocked by the antiestrogen tamoxifen. Both of these findings suggest that the classic estrogen receptor is not involved. On the other hand, DHT, which blocks the binding of estradiol to SHBG, completely negates the effect of estradiol on cAMP. Finally, the SHBG-estradiol-responsive second-messenger system has been primarily localized to the prostatic stromal cells and not to the epithelial cells.
Thus, estrogens may be causally linked to the onset of benign prostatic hyperplasia and may have an important supportive role in its maintenance. Aromatase inhibitors such as the investigational agent atamestane can produce marked reductions in both serum levels and intraprostatic concentrations of estrogens, including estradiol and estrone. However, to date, clinical trials with aromatase inhibitors for benign prostatic hyperplasia have been disappointing.
Evidence suggests that prostatic growth is under the direct control of specific growth factors and only indirectly modulated by androgens. According to this evidence, growth factors from both the fibroblast growth factor (FGF) family and the transforming growth factor (TGF) “superfamily” act together to regulate growth. These growth factors are polypeptides that modulate cell proliferation. The FGF family stimulates cell division and growth: Basic fibroblast growth factor (bFGF) stimulates growth of both stroma and blood vessels (angiogenesis), and fibroblast growth factor 7 (FGF7; also known as keratinocyte growth factor [KGF]) stimulates growth of epithelial cells. On the other hand, members of the TGF-β family inhibit cell division. TGF-β1 primarily inhibits growth of stroma, and TGF-β2 primarily inhibits growth of epithelial cells. In the normal prostate, the rate of cell death is equaled by the rate of cell production. It is hypothesized that a balance exists in the stroma between the stimulatory effects of bFGF and the inhibitory effects of TGF-β1 and in the epithelial glands between FGF7 stimulation and TGF-β2 inhibition. In benign prostatic hyperplasia, when excess growth of stroma predominates, bFGF is overproduced relative to its regulator TGF-β1; when excess growth of epithelial glands occurs, FGF7 is overproduced relative to TGF-β2.
Other growth factors, including epidermal growth factor and insulin-like growth factors (IGF-1 and IGF-2), are also known to stimulate prostatic tissue growth. The IGF axis has been implicated in the pathogenesis of benign prostatic hyperplasia via the paracrine action of IGFs and IGF-binding proteins (IGFBPs). It is hypothesized that DHT may increase IGF-2 activity, mainly in the periurethral region, which in turn induces benign proliferation of both epithelial and stromal cells, characteristic of benign prostatic hyperplasia. In normal prostatic stromal cells, TGF-β1 exerts its antiproliferative effects by stimulating the production of IGFBP-3, which acts as an inhibitory factor for cell growth, either indirectly, by inhibiting IGFs, or directly, by interacting with cells. In cells cultured from hyperplastic prostatic tissue, prostatic stromal cells have a reduced IGFBP-3 response to TGF-β1 and demonstrate decreased TGF-β1–induced growth inhibition relative to normal prostatic stromal cells. Growth factors undoubtedly also play a role in the development of bladder hypertrophy in response to outflow obstruction (see later). TGF-β is known to stimulate collagen synthesis and deposition in the bladder.
Targeting peptide growth factors offers a potential means of regulating prostatic enlargement and relieving symptoms associated with benign prostatic hyperplasia. Preliminary clinical trials of growth factor antagonists have led to significant improvements in urinary symptoms, maximal flow rates, and residual volumes.
Prostatic Smooth Muscle, Adrenergic Receptors, and Phosphodiesterase Type 5
Prostatic smooth muscle represents a significant proportion of the gland. Urethral elasticity and the degree of bladder outlet obstruction are undoubtedly influenced by the relative content of smooth muscle within the prostate in patients with benign prostatic hyperplasia. Undoubtedly, resting and dynamic prostatic smooth muscle tone plays a major role in the pathophysiology of benign prostatic hyperplasia. Smooth muscle cells in the prostate—at the bladder neck and in the prostatic capsule—are richly populated with α-adrenergic receptors. Contraction of the prostate and bladder neck are mediated by α1-adrenergic receptors. Stimulation of these receptors results in a dynamic increase in prostatic urethral resistance. Alpha1-adrenergic receptor blockade clearly diminishes this response and has been found to improve symptoms, urinary flow rates, and residual urine volumes in patients with benign prostatic hyperplasia within 2–4 weeks after start of therapy. The selective α1-blockers prazosin, terazosin, doxazosin, and alfuzosin have been extensively studied and found to be effective (Table 23–8). Because the bladder’s smooth muscle cells do not contain a significant number of α1 receptors, alpha-blocker therapy can selectively diminish urethral resistance without affecting detrusor smooth muscle contractility.
Table 23–8Alpha-receptor blockade for benign prostatic hyperplasia. |Favorite Table|Download (.pdf) Table 23–8 Alpha-receptor blockade for benign prostatic hyperplasia.
|Agent ||Site and Mechanism of Action ||Side Effects |
| ||Presynaptic and postsynaptic α1, α2 blockade ||Hypotension |
|Postsynaptic α1 blockade ||Hypotension (especially postural hypotension leading to syncope) |
| ||Postsynaptic α1a || |
Studies have suggested that the α1 receptors involved in the contraction of prostate smooth muscle appear to be α1a receptors (previously called α1c receptors). Clinical studies have established the efficacy of the subtype-selective α1a antagonist, tamsulosin and silodosin.
Contractile protein gene expression in stromal smooth muscle cells is significantly altered after alpha blockade. This suggests that alpha-blocking agents may work not only by the simple relaxation of muscle tone but also by affecting the phenotypic expression of contractile proteins in prostatic smooth muscle cells.
Alpha-blockers may also work by changing the balance between prostate cell growth and death. Some investigators hypothesize that benign prostatic hyperplasia occurs as a result of a decrease in apoptosis (programmed cell death), allowing more cells to accumulate in the prostate, hence causing its enlargement. The alpha-blockers doxazosin and terazosin have been shown to induce apoptosis in the stroma of the prostate.
Another means to relax smooth muscle and reduce symptoms of benign prostatic hyperplasia may be phosphodiesterase type 5 (PDE5) inhibitors. The PDE5 enzyme has been found throughout the urinary tract, where it works to break down the intracellular smooth muscle relaxant, cyclic guanosine monophosphate (cGMP). This means that PDE5 inhibition may reduce smooth muscle tone in the prostate, the urethra, and the bladder, although the exact mechanism of action in relation to urinary symptoms is still to be determined. Nevertheless, trials have shown that PDE5 inhibitors can improve urinary symptoms by approximately the same magnitude as alpha-blockers and may increase urinary flow.
Possible Mechanisms of Bladder Outlet Obstruction
There are several ways in which benign prostatic hyperplasia might cause obstruction of the bladder neck. The prominent median lobe may simply act as a ball valve, restriction may occur from the nondistensible capsule, static obstruction may result from the enlarged prostate surrounding the prostatic urethra, and dynamic obstruction may occur from inability to relax prostatic smooth muscle. In fact, clinical data support a role for each of these proposed factors. For example, TURP frequently relieves obstructive symptoms, as does simple surgical incision of the prostatic capsule. Medications that shrink the prostate or relax smooth muscle also relieve bladder outlet obstruction and increase urinary flow rates.
Various thermal therapies have been investigated as less invasive surgical procedures than TURP for benign prostatic hyperplasia, including transurethral microwave, high-intensity focused ultrasound, laser-delivered interstitial thermal therapies, and transurethral needle ablation (TUNA) of the prostate. These procedures use different forms of energy such as microwave, ultrasound, laser, and radiofrequency to produce the thermal injury. It is unclear whether these procedures work by anatomic shrinkage or debulking of the obstructing enlarged prostate or by physiologic alteration of voiding function. In pathologic studies of TUNA of the prostate, for example, coagulative necrosis gradually changes to retractile fibrous scar. This could cause a decrease in the volume of the treated area even without a significant decrease in prostatic volume. Alternatively, severe thermal damage to intraprostatic nerve fibers may reduce the dynamic component of the bladder outlet obstruction by denervation of receptors or sensory nerves.
Bladder Response to Obstruction
Many of the clinical symptoms of benign prostatic hyperplasia are related to obstruction-induced changes in bladder function rather than to outflow obstruction per se. Thus, one-third of men continue to have significant voiding problems even after surgical relief of obstruction. Obstruction-induced changes in bladder function are of two basic types. First, there are changes that lead to detrusor overactivity (instability). These are clinically manifested by frequency and urgency. These two symptoms cause much of the distress related to benign prostatic hyperplasia and are sometimes quite out of proportion to the degree of obstruction. Thus, treatment of the bladder overactivity may have more impact than treatment of the obstruction. Second, there are changes that lead to decreased detrusor contractility. These are clinically manifested by symptoms of decreased force of the urinary stream, hesitancy, intermittency, increased residual urine, and, in a minority of cases, detrusor failure.
The bladder’s response to obstruction is largely adaptive (Figure 23–14). The initial response is the development of detrusor smooth muscle hypertrophy. It is hypothesized that this increase in muscle mass, though an adaptive response to increased intravesical pressure and one that maintains urinary outflow, is associated with significant intracellular and extracellular changes in smooth muscle cells that predispose to detrusor instability. In experimental animal models, unrelieved obstruction results in significant increases in detrusor extracellular matrix (collagen).
Schematic of natural history of benign prostatic hyperplasia. (Redrawn, with permission, from McConnell JD. The pathophysiology of benign prostatic hyperplasia. J Androl. 1991 Nov-Dec;12(6):356–63.)
In addition to obstruction-induced changes in the smooth muscle cells and extracellular matrix of the bladder, there is increasing evidence that chronic obstruction in patients with untreated benign prostatic hyperplasia may alter neural responses as well, occasionally predisposing to detrusor failure.
Traditional therapies for symptoms associated with bladder obstruction have been directed toward relief of bladder outflow resistance. New treatments of obstructive detrusor instability have been suggested using drugs that are autonomically active (such as α1 antagonists) and drugs that stabilize muscle cell membranes (such as anticholinergic agents). In the past, anticholinergic drugs were avoided because of fear that inhibiting bladder activity would lead to acute urinary retention, but that fear has not been substantiated in recent studies.
The effects of chronic obstruction on the bladder are still not well understood. Future studies must examine the importance of changes in receptor density, affinity, and distribution as well as agonist release and degradation that occur during chronic obstruction and the ultrastructural and physiologic changes that occur with relief of obstruction.
Obstruction to urinary outflow and bladder dysfunction is responsible for the major symptoms and signs of benign prostatic hyperplasia. Prostatic enlargement may cause either acute or chronic urinary retention. With acute urinary retention, there is painful dilation of the bladder, with inability to void. Acute urinary retention is often precipitated by swelling of the prostate caused by infarction of a nodule or by certain medications. With chronic urinary retention, there are both obstructive and irritative voiding symptoms. Occasionally, a patient presents with marked urinary retention, yet few if any symptoms.
There are two types of symptoms: irritative, which are related to bladder filling, and obstructive, which are related to bladder emptying. Irritative symptoms occur as a consequence of bladder hypertrophy and dysfunction and include urinary frequency, nocturia, and urgency. These observations may be more related to the bladder’s response to the obstruction, rather than to direct effects of the obstruction itself. Obstructive symptoms result from distortion and narrowing of the bladder neck and prostatic urethra, leading to incomplete emptying of the bladder. Obstructive symptoms include difficulty initiating urination, decreased force and caliber of the urinary stream, intermittency of the urinary stream, urinary hesitancy, and dribbling.
To evaluate objectively the severity and complexity of symptoms in benign prostatic hyperplasia, a symptom index has been developed by the American Urologic Association. The self-administered questionnaire evaluates patient symptoms, such as bladder emptying, frequency, intermittency, urgency, and nocturia, as well as quality of life. The symptom index has been validated and found to have good test-retest reliability and to discriminate well between affected patients and controls. In clinical trials, there have been good correlations between urinary symptoms and the total score, and the instrument has proved useful to describe changes in symptoms over time and after treatment.
Complications of the chronic bladder dilation include hypertrophy of the bladder wall musculature and development of diverticula; urinary tract infection of the stagnant bladder urine; hematuria, particularly with infarction of a prostatic nodule; and chronic kidney disease and azotemia from bilateral hydroureter and hydronephrosis. The most troublesome symptom that patients may experience from chronic bladder dilation is the inability to urinate on command. This can be treated by teaching the patient the technique of intermittent self-catheterization to empty the bladder about every 4 hours.
Digital rectal examination may reveal either focal or diffuse enlargement of the prostate. However, the size of the prostate as estimated by digital rectal examination does not correlate well with either the symptoms or signs of benign prostatic hyperplasia or the need for treatment. Examination of the lower abdomen may reveal a distended bladder, consistent with urinary retention, which may occur silently in the absence of severe symptoms.
Laboratory Tests and Evaluation
Laboratory tests performed to evaluate patients with benign prostatic hyperplasia include blood urea nitrogen (BUN) and serum creatinine to exclude renal failure and urinalysis and urine culture to exclude urinary tract infection. Elevations of BUN or serum creatinine from benign prostatic hyperplasia occur only rarely. Intravenous pyelography (IVP) or ultrasound is usually not performed in patients with normal findings on these simple laboratory tests. Instead, it is generally reserved for patients with hematuria or suspected hydronephrosis. When an IVP or ultrasound is performed in men with benign prostatic hyperplasia, it typically shows elevation of the bladder base by the enlarged prostate; trabeculation, thickening, and diverticula of the bladder wall; elevation of the ureters; and poor emptying of the bladder. Uncommonly, in a neglected patient, the IVP or ultrasound shows hydronephrosis, putting him at risk for acute kidney failure.
The most useful technique for assessing the significance of benign prostatic hyperplasia is urodynamic evaluation with uroflowmetry and cystometry. In these tests, the patient voids and various measurements are made. In uroflowmetry, the maximal urinary flow rate is recorded. If the peak flow rate is less than 10 mL/s, the patient is considered to have significant bladder outlet obstruction. However, the patient must void at least 150 mL for the measurement to be considered reliable. Pressure-flow studies are simultaneous recordings of urinary bladder pressure and urinary flow rates, which provide information about urethral resistance. These pressure flow studies can help in finding those patients that are less likely to benefit from prostatic surgery by providing information on detrusor function. Cystourethroscopy is usually reserved for patients who have hematuria that remains unexplained despite an IVP or ultrasound or preoperatively for patients who require TURP. Validated symptom scores, estimation of prostate volume, and determination of serum prostate-specific antigen can help to predict the progression of benign prostatic hyperplasia. New ultrasound techniques also hold promise.
Which is the major androgen controlling prostate size?
What are some of the different ways in which androgens can be suppressed to decrease prostate size and obtain at least temporary relief of obstructive symptoms?
What are the effects of antiestrogen treatment on males with benign prostatic hyperplasia?
What is the role of α1-adrenergic receptors in benign prostatic hyperplasia?
What are some bladder changes that occur in patients with benign prostatic hyperplasia?
What are some symptoms and signs of benign prostatic hyperplasia?
How is the diagnosis of benign prostatic hyperplasia made?