Conditions that cause infertility that act at the pretesticular level tend to be hormonal in nature (Table 44–11).
Table 44–11. Pretesticular Causes of Infertility. ||Download (.pdf)
Table 44–11. Pretesticular Causes of Infertility.
Gonadotropin deficiency (Kallmann syndrome)
Isolated LH deficiency (“fertile eunuch”)
Isolated FSH deficiency
Congenital hypogonadotrophic syndromes
Pituitary insufficiency (tumors, infiltrative processes, operation, radiation, deposits)
Exogenous hormones (estrogen–androgen excess, glucocorticoid excess, hyper- and hypothyroidism)
Growth horm one deficiency
Gonadotropin Deficiency (Kallmann Syndrome)
Kallmann syndrome (1:30,000) is characterized by central hypogonadism, delayed in puberty, and infertility. Other clinical features include anosmia, small testes and occasionally renal agenesis, bimanual synkinesia, cleft lip, and dental agenesis. When anosmia is not present, the condition is termed idiopathic hypogonadotrophic hypogonadism (IHH). The clinical diagnosis of Kallmann syndrome is confirmed by hormonal assessment revealing low testosterone, low LH, low FSH, and normal prolactin levels. Infertility is treatable with gonadotropin (LH and FSH) replacement over 12–18 months, which induces sperm in the ejaculate in 80% of men. The condition is inherited as a familial disorder in one-third of cases and both X-linked and autosomal inheritance patterns have been described. In the X-linked recessive form, deletions of the KAL1 gene prevent migration of GnRH neurons to the preoptic area of the hypothalamus during embryologic development.
Isolated Gonadotropin Deficiencies
These deficiencies are rare. As the result of a partial LH deficit, there is enough LH to stimulate intratesticular testosterone production and spermatogenesis but insufficient testosterone to promote virilization. The results are a eunuchoid body habitus, variable virilization, and gynecomastia. These men usually have normal size testes, but sperm concentration is low. Plasma FSH levels are normal, but serum LH and testosterone levels are low normal.
With insufficient FSH production by the pituitary, patients are normally virilized, testicular size is normal, and LH and testosterone levels are normal. FSH levels are uniformly low and do not respond to stimulation with GnRH. Sperm counts range from azoospermia to severely low numbers (oligospermia).
Congenital Hypogonadotrophic Syndromes
Several syndromes may be associated with secondary hypogonadism. Prader–Willi syndrome (1:20,000) is characterized by obesity, mental retardation, small extremities, and hypogonadism and is caused by a deficiency of hypothalamic GnRH. The cause of this condition appears to be a single gene deletion on chromosome 15. Similar to Kallmann syndrome, spermatogenesis can be induced by treatment with FSH and LH. Bardet–Biedl syndrome is an autosomal recessive form of hypogonadotrophic hypogonadism that also results from GnRH deficiency. It is characterized by mental retardation, retinitis pigmentosa, polydactyly, and hypogonadism. The presentation is similar to Kallmann syndrome but includes obesity and may also be treated with gonadotropin administration. Cerebellar ataxia can be associated with hypogonadotrophic hypogonadism. Cerebellar involvement includes abnormalities of speech and gait and these patients can have a eunuchoid appearance with atrophic testes. Hypothalamic–pituitary dysfunction due to pathologic changes in cerebral white matter is thought to underlie infertility.
Pituitary insufficiency may result from tumors, infarcts, surgery, radiation, or infiltrative and granulomatous processes. In sickle cell anemia, pituitary and testicular microinfarcts result from sickling of red blood cells potentially leading to both hypogonadism and spermatogenic failure. Men with sickle cell anemia have decreased testosterone and variable LH and FSH levels. Beta-thalassemia occurs primarily in patients of Mediterranean or African origin and is caused by mutations in the beta-globulin that leads to abnormal hemoglobin composition and subsequent red cell lysis. Infertility results from the deposition of hemosiderin in the pituitary gland and testes. Similarly, hemochromatosis results in iron deposition within the liver, testis, and pituitary and is associated with testicular dysfunction in 80% of cases.
Elevations of circulating prolactin can cause hypogonadotropic hypogonadism. If hyperprolactinemia is identified, secondary causes such as stress during the blood draw, systemic illness, or medications should be ruled out. With these causes excluded, the most common and important cause of hyperprolactinemia is a prolactin-secreting pituitary adenoma, or prolactinoma. MRI of the sella turcica has classically been used to distinguish between microadenoma (<10 mm) and macroadenoma (>10 mm) forms of tumor.
Stratification of disease based on radiologic diagnosis alone is misleading, as surgery for hyperprolactinemia almost always reveals a pituitary tumor. Elevated prolactin typically results in suppression of gonadotropin production, with subsequent declines in testosterone levels and spermatogenesis. Symptoms of hyperprolactinemia may include loss of libido, erectile dysfunction, gynecomastia, and galactorrhea. Signs and symptoms of other pituitary hormone derangements (adrenocorticotropic hormone, thyroid-stimulating hormone) should also be investigated.
Exogenous or Endogenous Hormones
An excess of sex steroids, either estrogens or androgens, may cause infertility due to an imbalance of the testosterone estrogen ratio, which is normally 10:1. Liver cirrhosis increases endogenous estrogens due to augmented aromatase activity within the diseased liver. Likewise, obesity may be associated with testosterone and estrogen imbalance owing to increased peripheral aromatase activity in adipocytes. Less commonly, adrenocortical tumors, Sertoli cell tumors, and interstitial testis tumors may produce estrogens. Excess estrogens cause spermatogenic failure by decreasing pituitary gonadotropin secretion, thus inducing secondary testis failure.
An excess of androgens can suppress pituitary gonadotropin secretion and lead to secondary testis failure. The use of exogenous androgenic steroids (anabolic steroids) by as many as 15% of high school athletes, 30% of college athletes, and 70% of professional athletes may result in temporary sterility due to suppression of the normal HPG axis. Treatment includes immediate discontinuation of steroids and reevaluation of semen quality every 3–6 months until spermatogenesis returns. The most common reason for excess endogenous androgens is congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. The resultant absence of cortisol synthesis and excessive adrenocorticotropic hormone production leads to elevated androgenic steroids by the adrenal cortex. High androgen levels in prepubertal boys result in precocious puberty, with premature development of secondary sex characteristics and abnormal enlargement of the phallus. The testes are characteristically small because of central gonadotropin inhibition by androgens. In young girls, virilization occurs with clitoral enlargement. In cases of classic congenital adrenal hyperplasia that presents in childhood, normal sperm counts and fertility have been reported, even without glucocorticoid treatment. This disorder is one of the few intersex conditions associated with potentially normal fertility. Other sources of endogenous androgens include hormonally active adrenocortical tumors or Leydig cell tumors of the testis.
Hyper- and Hypothyroidism
Thyroid abnormalities are a rare cause (0.5%) of male infertility. Abnormally high or low levels of serum thyroid hormone impact spermatogenesis at the level of both the pituitary and testis. Euthyroidism is important for normal hypothalamic hormone secretion and for normal sex hormone–binding protein levels that govern the testosterone–estrogen ratio.
Many conditions that cause infertility act at the testicular level (Table 44–12.) Unlike many pretesticular conditions, which are treatable with hormonal manipulation, testicular defects are mostly irreversible.
Table 44–12. Testicular Causes of Infertility. ||Download (.pdf)
Table 44–12. Testicular Causes of Infertility.
Chromosomal (Klinefelter syndrome [XXY], XX sex reversal, XYY syndrome)
Noonan syndrome (male Turner syndrome)
Vanishing testis syndrome (bilateral anorchia)
Sertoli-cell-only syndrome (germ cell aplasia)
Y chromosome microdeletions (DAZ)
Gonadotoxins (radiation, drugs)
Systemic disease (renal failure, liver failure, sickle cell anemia)
Defective androgen activity
Testis injury (orchitis, torsion, trauma)
Y Chromosome Microdeletions
Approximately 7% of men with low sperm counts and 13% of men with azoospermia have a structural alteration in the long arm of the Y chromosome (Yq). The testis-determining region genes that control testis differentiation are intact, but there may be gross deletions in other regions that may lead to defective spermatogenesis. The recent explosion in molecular genetics has allowed for sophisticated analysis of the Y chromosome. At present, three gene sites are being investigated as putative AZF (azoospermia factor) candidates: AZFa, b, and c. The most promising site is AZFc, which contains the DAZ gene region. The gene, of which there are at least six copies in this region, appears to encode a ribonucleic acid (RNA)-binding protein that regulate the meiotic pathway during germ cell production. Homologs of the DAZ gene are found in many other animals, including mouse and Drosophila. A quantitative polymerase chain reaction–based assay is used to test blood for these deletions. In the future, sperm DNA may also be tested as part of a semen analysis. Since men with these microdeletions can have sperm in the ejaculate, they are likely to pass them on to offspring if ART is used.
Abnormalities in chromosomal constitution are well-recognized causes of male infertility. In a study of 1263 infertile couples, a 6.2% overall prevalence of chromosomal abnormalities was detected. Among men whose sperm count was <10 million/mL, the prevalence was 11%. In azoospermic men, 21% had significant chromosomal abnormalities. For this reason, cytogenetic analysis (karyotype) of autosomal and sex chromosomal anomalies should be considered in men with severe oligospermia and azoospermia.
Klinefelter syndrome is the most common chromosomal aneuploidy and a common genetic cause of azoospermia, accounting for up to 14% of cases in some series (overall incidence 1:500 males). The classic triad of findings is small, firm testes; gynecomastia; and azoospermia. Some men may present with delayed sexual maturation, increased height, decreased intelligence, varicosities, obesity, diabetes, leukemia, increased likelihood of extragonadal germ cell tumors, and breast cancer (20-fold higher than in normal men). Among men with Klinefelter syndrome, 90% have an extra X chromosome (47,XXY) and 10% are mosaic, with a combination of XXY/XY chromosomes. The testes are usually <2 cm in length and always <3.5 cm; biopsies show sclerosis and hyalinization of the seminiferous tubules with normal numbers of Leydig cells. Hormones usually demonstrate decreased testosterone and frankly elevated LH and FSH levels. Serum estradiol levels may also be elevated. With age, testosterone levels decline, and most men will require androgen replacement therapy both for virilization and for normal sexual function. Paternity with this syndrome is rare but more likely in the mosaic or milder form of the disease. Some men will have limited spermatogenesis, whereby sperm may be retrieved from the testicles and used with ICSI to cause pregnancy.
Other Genetic Causes and Syndromes
XX male syndrome is a structural and numerical chromosomal condition, a variant of Klinefelter syndrome that presents as gynecomastia at puberty or as azoospermia in adults. Average height is below normal, and hypospadias is common. Male external and internal genitalia are otherwise normal. The prevalence of mental deficiency is not increased. Hormone evaluation shows elevated FSH and LH and low or normal testosterone levels. Testis biopsy reveals absent spermatogenesis with fibrosis and Leydig cell clumping. The most obvious explanation is that sex-determining ratio (SRY), or the testis-determining region, is translocated from the Y to the X chromosome. Thus, testis differentiation is present; however, the genes that control spermatogenesis on the Y chromosome are not similarly translocated, resulting in azoospermia.
The prevalence of XYY syndrome is similar to that of Klinefelter, but the clinical presentation is more variable. Typically, men with 47,XYY are tall, and 2% exhibit aggressive or antisocial behavior. Hormone evaluation reveals elevated FSH and normal testosterone and LH levels. Semen analyses show either oligospermia or azoospermia. Testis biopsies vary but usually demonstrate arrest of maturation or Sertoli-cell-only syndrome.
Also called male Turner syndrome, Noonan syndrome is associated with clinical features similar to Turner syndrome (45,X). However, the karyotype is either normal (46,XY) or mosaic (X/XY). Typically, patients have dysmorphic features like webbed neck, short stature, low-set ears, wide-set eyes, and cardiovascular abnormalities. At birth, 75% have cryptorchidism that limits fertility in adulthood. If testes are fully descended, then fertility is possible and likely. Associated FSH and LH levels depend on the degree of testicular function.
Myotonic dystrophy is the most common reason for adult-onset muscular dystrophy. In addition to having myotonia, or delayed relaxation after muscle contraction, patients usually present with cataracts, muscle atrophy, and various endocrinopathies. Most men have testis atrophy, but fertility has been reported. Infertile men may have elevated FSH and LH with low or normal testosterone, and testis biopsies show seminiferous tubule damage in 75% of cases. Pubertal development is normal; testis damage seems to occur later in life.
Vanishing Testis Syndrome
Also called bilateral anorchia, vanishing testis syndrome is rare, occurring in 1:20,000 males. Patients present with bilateral nonpalpable testes and sexual immaturity due to the lack of testicular androgens. The testes are lost due to fetal torsion, trauma, vascular injury, or infection. In general, functioning testis tissue must have been present during weeks 14–16 of fetal life, since Wolffian duct growth and Müllerian duct inhibition occur along with appropriate growth of male external genitalia. Patients have eunuchoid body proportions but no gynecomastia. The karyotype is normal. Serum LH and FSH levels are elevated, and serum testosterone levels are extremely low. There is no treatment for this form of infertility; patients receive lifelong testosterone for normal virilization and sexual function.
Sertoli-cell-only syndrome is characterized by the complete absence of germinal cells on histologic examination of testes biopsies from an azoospermic man. Several causes have been proposed, including genetic defects, congenital absence of normal germ cell migration during embryogenesis, and androgen resistance. Clinically, men are normally virilized with smaller than normal testes with normal consistency. Endocrine function of the testes is preserved and testosterone and LH levels are normal; however, FSH levels are usually (90%) elevated. The use of the word “syndrome” implies that no recognized insult has occurred, since gonadotoxins such as ionizing radiation, chemotherapy, and mumps orchitis can also render the testes aplastic of germ cells. There is no known treatment for this condition. In some patients, extensive testis sampling with FNA mapping or multiple biopsies can reveal sperm that can be used for pregnancy with ARTs.
Defective DNA Mismatch Repair
Defective DNA repair has been suspected to play an etiologic role in certain cancers. Data from mice suggest that mutations in genes needed for DNA repair (PMS2, Mlh1) also lead to infertility characterized by meiotic arrest with a pattern of maturation arrest seen in testis pathology. Male infertility characterized by azoospermia and both germ cell maturation arrest and Sertoli-cell-only syndrome has also been described in association with abnormalities in DNA mismatch repair. This provides evidence that certain forms of male infertility could involve the inability to properly repair germline DNA. The relationship between defective DNA repair in infertile men and their risk of cancer as well as the risk of cancer among their biological offspring certainly merits further research.
The effects of radiotherapy on sperm production have been well described. Clifton and Bremner (1983) examined the effects of ionizing irradiation on semen quality and spermatogenesis among a population of healthy prisoners in the 1960s. Before a vasectomy, each of the volunteers was exposed to various levels of radiation and found a distinct dose-dependent, inverse relationship between irradiation and sperm count. Sperm count was significantly reduced at 15 cGy, and azoospermia was temporarily induced at 50 cGy. Persistent azoospermia was induced at 400 cGy, without evidence of recovery for a minimum of 40 weeks. In most subjects, sperm counts rebounded to preirradiation levels with cessation of exposure.
Histologic examination of testis tissue after irradiation has shown that spermatogonia are most sensitive to irradiation while Leydig cell mass is relatively preserved. Given the sensitivity of germ cells to irradiation, some studies have focused on the testicular radiation exposure that occurs during radiation therapy for cancer. During abdominal radiation with gonadal shielding, the estimated mean unintended gonadal exposure is approximately 75 cGy. There does not appear to be an increase in congenital birth defects in offspring of irradiated men. Importantly, recent data have suggested that environmental or occupational exposure to electromagnetic radiation may also reduce semen quality.
A list of gonadotoxic medications can be found in Table 44–13. These can result in infertility by various mechanisms. Ketoconazole, spironolactone, and alcohol inhibit testosterone synthesis, whereas cimetidine is an androgen antagonist. Recreational drugs such as marijuana, heroin, and methadone are associated with lower testosterone levels. Certain pesticides, like dibromochloropropane, are likely to have estrogen-like activity. Importantly, the gonadotoxic potential of many pharmaceutical and over-the-counter medications is unknown. Therefore, couples should consider discontinuing and unnecessary medication or supplements prior to their attempt to conceive.
Table 44–13. Medications Associated with Infertility.
Chemotherapies intended for their cytotoxic effects on rapidly dividing cancer cells also have a profound impact on germ cells that are normally dividing at a rapid rate. Spermatogonia are the germ cells most sensitive to cytotoxic chemotherapy. Alkylating agents such as cyclophosphamide, chlorambucil, and nitrogen mustard are the most toxic agents. The effects of chemotherapeutic drugs vary according to dose and duration of treatment, type and stage of disease, age and health of the patient, and baseline testis function. Despite this toxicity, the mutagenic effects of chemotherapy agents do not appear to be significant enough to increase the chance of birth defects or genetic diseases among offspring of treated men. Patients should wait at least 6 months after chemotherapy ends before attempting to conceive.
Uremia is associated with infertility, decreased libido, erectile dysfunction, and gynecomastia. The cause of hypogonadism is controversial and probably multifactorial. Testosterone levels are decreased, and FSH and LH levels can be elevated. Serum prolactin levels are elevated in 25% of patients. Hyperestrogenemia may play a role in hormone axis derangements and impaired spermatogenesis. Medications and uremic neuropathy may cause uremic-related impotence and a decline in libido. Renal transplantation can result in improvement in hypogonadism.
Hypogonadism related to liver failure may have various contributing factors. The reason for organ failure is important. Hepatitis is associated with viremia, and associated fevers can affect spermatogenesis. Excessive alcohol intake inhibits testicular testosterone synthesis, independent of its liver effects. Liver failure and cirrhosis are associated with testicular atrophy, impotence, and gynecomastia. Levels of testosterone and its metabolic clearance are decreased; estrogen levels are increased owing to augmented conversion of androgens to estrogens by aromatase. Decreased testosterone levels are not accompanied by proportionate elevations in LH and FSH levels, suggesting that a central inhibition of the HPG axis may accompany liver failure.
As mentioned earlier, sickle cell disease can cause pituitary dysfunction, likely due to the sludging of erythrocytes and associated microinfarcts. This same mechanism may also occur in testis tissue and contribute to primary hypogonadism. As a result, spermatogenesis is decreased, accompanied by lower serum testosterone levels.
Prolonged diabetes can result in significant cardiovascular disease, as well as peripheral neuropathy. The impact of such disease on erectile and ejaculatory function has been well described. In addition to poor sexual function, neuropathy involving the parasympathetic and sympathetic pelvic plexus can lead to poor contractility of the bladder neck and ejaculatory organs resulting in retrograde or anejaculation.
Defective Androgen Activity
Peripheral resistance to androgens occurs with two basic defects: (1) a deficiency of androgen production through the absence of 5-alpha-reductase and (2) a deficiency in the androgen receptor. In general, these conditions are a consequence of single gene deletions.
5-Alpha-reductase deficiency results in normal development of the testes and Wolffian duct structures (internal genitalia) but ambiguous external genitalia. The ambiguity results from an inborn deficiency of the 5-alpha-reductase enzyme that converts testosterone to DHT in androgen-sensitive tissues like the prostate, seminal vesicle, and external genitalia. Thus far, 29 mutations have been described in the culprit enzyme. The diagnosis is made by measuring the ratio of testosterone metabolites in urine and confirmed by finding decreased 5-alpha-reductase in genital skin fibroblasts. Spermatogenesis has been described in descended testes; however, fertility has not been reported in these patients. The lack of fertility may be due largely to functional abnormalities of the external genitalia.
Androgen Receptor Deficiency
Androgen receptor deficiency is an X-linked genetic condition marked by resistance to androgens. The androgen receptor, a nuclear protein, is absent or functionally altered such that testosterone or DHT cannot bind to it and activate target cell genes. Since androgens have no effect on tissues, both internal and external genitalia are affected. Fertility effects depend on the specific receptor abnormality. Some patients are 46,XY males with complete end-organ resistance to androgens. They have female external genitalia with intra-abdominal testes. Testes show immature tubules and the risk of testis cancer is elevated: Tumors will develop in 10–30% of patients without orchiectomy. Fertility is absent. Patients with mild receptor defects may present as normal-appearing infertile men. Spermatogenesis may be present, although impaired. It is unclear exactly how common this occurs in infertile men.
Inflammation of testis tissue is most commonly due to bacterial infection, termed epididymo-orchitis. Viral infections also occur in the testis in the form of mumps orchitis. Orchitis is observed in approximately 30% of postpubertal males who develop mumps parotitis. Testis atrophy is a significant and frequent result of viral orchitis but is less common with bacterial infections.
Ischemic injury to the testis secondary to twisting of the testis on the spermatic cord pedicle is common in prepubertal and early postpubertal boys. When diagnosed and corrected surgically within 6 hours of occurrence, the testis can usually be saved. Torsion may result in inoculation of the immune system with testis antigens that may predispose to later immunological infertility. It recognized that the “normal” contralateral mate of a torsed testis could also exhibit histologic abnormalities. It has not been clearly demonstrated whether this is related to the actual torsion or to an underlying abnormality in testes predisposed to torsion.
Trauma to the testis can result in infertility. Because of the unique immunologic status of the testis in the body (ie, it is an immunologically privileged site), trauma to the testis can invoke an abnormal immune response in addition to atrophy resulting from injury. Both may contribute to infertility. Trauma to the testis that results in fracture of the testis tunica albuginea should be surgically explored and repaired to minimize exposure of testis tissue to the body.
Undescended testis is a common urologic problem, observed in 0.8% of boys at 1 year of age. It is considered a developmental defect and places the affected testis at higher risk of developing testicular germ cell cancer. Although the newborn undescended testis is morphologically normal, deterioration in germ cell numbers is often seen by 2 years of age. The contralateral, normally descended testis is also at increased risk of harboring germ cell abnormalities. Thus, males with either unilaterally or bilaterally undescended testes are at risk for infertility later in life. Historically, orchidopexy was performed solely for the purpose of testicle palpation to allow for cancer detection. However, more recent data have shown that when performed prior to puberty, orchidopexy reduces the risk of cancer development. Other data have suggested that early orchidopexy can improve spermatogenesis in cryptorchid boys.
Varicocele is defined as dilated and incompetent veins within the pampiniform plexus of spermatic cord. Varicocele has been described as the most common surgically correctable cause of male subfertility. This is a disease that develops during puberty when both endocrine and exocrine function of the testicle dramatically increases, along with testicular blood flow. Varicocele is only rarely detected in boys <10 years of age. A left-sided varicocele is found in 15% of healthy young men. In contrast, the incidence of a left varicocele in subfertile men approaches 40%. Bilateral varicoceles are uncommon in healthy men (<10%) but are palpated in up to 20% of subfertile men. In general, varicoceles do not spontaneously regress. An accurate physical examination remains the cornerstone of varicocele diagnosis.
Several anatomic features contribute to the predominance of left-sided varicoceles. The left internal spermatic vein is longer than the right and it typically joins the left renal vein at a right angle compared with the oblique insertion of the right spermatic vein into the inferior vena cava. As a result of these characteristics, higher venous pressures fare transmitted to the left spermatic cord veins and result in retrograde reflux of blood.
Varicoceles are associated with testicular atrophy and varicocele correction can reverse atrophy in adolescents. There is strong evidence that the varicocele affects semen quality. Varicocele can cause abnormalities in concentration, motility, and morphology; however, deficits in motility can be the most profound. The finding of semen abnormalities constitutes the most common indication for varicocele surgery in infertile men.
The mechanism by which varicocele exerts an effect on the testicle remains unclear. Several theories have been postulated and it is likely that a combination of effects results in infertility. Pituitary–gonadal hormonal dysfunction, internal spermatic vein reflux of renal or adrenal metabolites, and an increase in hydrostatic pressure associated with venous reflux are also postulated effects of a varicocele. The most intriguing theory of how varicoceles affect testis function invokes an inhibition of spermatogenesis through the reflux of warm corporeal blood around the testis, with disruption of the normal countercurrent heat exchange balance and elevation of intratesticular temperature.
It has been estimated that nearly half of male infertility has no readily identifiable cause. The etiology of male infertility is likely multifactorial, encompassing genetic, endocrine, and environmental factors. In addition, modifiable lifestyle characteristics may make a significant contribution to the disease. The effects of physical activity, obesity, alcohol and tobacco use, psychological stress, and cell phone usage on male infertility have been examined in a few observational studies, yet results are inconclusive due to limitations in study design.
Posttesticular (Table 44–14)
Table 44–14. Posttesticular Causes of Infertility. ||Download (.pdf)
Table 44–14. Posttesticular Causes of Infertility.
Reproductive tract obstruction
Congenital absence of the vas deferens (CAVD)
Idiopathic epididymal obstruction
Polycystic kidney disease
Ejaculatory duct obstruction
Sympathetic nerve injury
Disorders of sperm function or motility
Immotile cilia syndromes
Disorders of coitus
Timing and frequency
Reproductive Tract Obstruction
The posttesticular portion of the reproductive tract includes the epididymis, vas deferens, seminal vesicles, and associated ejaculatory apparatus.
CF is the most common autosomal recessive genetic disorder in the United States with a carrier frequency of 1:20 among Caucasians. The disease is caused by defective chloride ion transport across cell membranes resulting in fluid and electrolyte abnormalities (abnormal chloride–sweat test). CF typically presents with chronic lung obstruction and pulmonary infections, pancreatic insufficiency, and infertility. More than 95% of men with CF also have congenital bilateral absence of the vas deferens (CBAVD). In addition to the vas, parts of the epididymis, seminal vesicles, and ejaculatory ducts may be atrophic or absent, causing obstruction. Although spermatogenesis is quantitatively normal, recent data suggest that sperm from men with CF may lack the normal capacity to fertilize an egg. Furthermore, some carriers of abnormal CF genes may also have functional sperm defects. CBAVD accounts for 1–2% of infertility cases. On physical examination, no palpable vas deferens is observed on one or both sides. As in CF, the rest of the reproductive tract ducts may also be abnormal and unreconstructable. This disease is related to CF. Even though most of these men demonstrate no symptoms of CF, up to 80% of patients will harbor a detectable CF mutation. In addition, 15% of these men will have renal malformations, most commonly unilateral agenesis.
Young syndrome presents with a triad of chronic sinusitis, bronchiectasis, and OA. The obstruction is in the epididymis. The pathophysiology of the condition is unclear but may involve abnormal ciliary function or abnormal mucus quality. Reconstructive surgery is associated with lower success rates than that observed with other obstructed conditions.
Idiopathic Epididymal Obstruction
Idiopathic epididymal obstruction is a relatively uncommon condition found in otherwise healthy men. There is recent evidence linking this condition to CF in that one-third of men so obstructed may harbor CF gene mutations.
Adult Polycystic Kidney Disease
Adult polycystic kidney disease is an autosomal dominant disorder associated with numerous cysts of the kidney, liver, spleen, pancreas, epididymis, seminal vesicle, and testis. Disease onset usually occurs in the twenties or thirties with symptoms of abdominal pain, hypertension, and renal failure. Infertility with this disease is usually secondary to obstructing cysts in the epididymis or seminal vesicle.
Blockage of the Ejaculatory Ducts
Blockage of the ejaculatory ducts, the delicate, paired, collagenous tubes that connect the vas deferens and seminal vesicles to the urethra, is termed EDO. It is the cause of infertility in 5% of azoospermic men. Obstruction can be congenital and result from Müllerian duct (utricular) cysts, Wolffian duct (diverticular) cysts, or congenital atresia or is acquired from seminal vesicle calculi or postsurgical or inflammatory scar tissue. It presents as hematospermia, painful ejaculation, or infertility. The diagnosis is confirmed by finding a low-volume ejaculate and TRUS showing dilated seminal vesicles or dilated ejaculatory ducts.
Vasectomy is performed on more than ½ million men per year in the United States for contraception. Subsequently, 6% of these men have the vasectomy reversed, most commonly because of remarriage.
Groin and hernia surgery can result in inguinal vas deferens obstruction in 1% of cases. There has been concern that Marlex mesh used for hernia repairs may add to perivasal inflammation and increase the likelihood of vassal obstruction.
Bacterial infections (E. coli in men age >35 or Chlamydia trachomatis in young men) may involve the epididymis, with scarring and obstruction.
Besides physical obstruction, functional obstruction of the seminal vesicles may exist. Functional blockages may result from nerve injury or medications that impair the contractility of seminal vesicle or vasal musculature. A classic example of nerve injury affecting ejaculation is after retroperitoneal lymph node dissection for testis cancer. This can cause either retrograde ejaculation or complete anejaculation, depending on the degree of injury to postganglionic sympathetic fibers arising from the thoracolumbar spinal cord. These autonomic nerves overlie the inferior aorta and coalesce as the hypogastric plexus within the pelvis and control seminal emission. Multiple sclerosis and diabetes are other conditions that result in disordered ejaculation.
Evidence from animal models indicates that the seminal vesicles possess contractile properties similar to those of the urinary bladder, suggesting that seminal vesicle organ dysfunction may underlie some cases of ejaculatory duct “obstruction.” Medications implicated in this functional problem are those classically associated with ejaculatory impairment. Table 44–5 lists these medications.
Disorders of Sperm Function or Motility
Immotile cilia syndromes are a heterogeneous group of disorders (1:20,000 males) in which sperm motility is reduced or absent. The sperm defects are due to abnormalities in the motor apparatus or axoneme of sperm and other ciliated cells. Normally, nine pairs of microtubules are organized around a central microtubule pair within the sperm tail and are connected by dynein arms (ATPase) that regulate microtubule and therefore sperm tail motion. Various defects in the dynein arms cause deficits in ciliary and sperm activity. Kartagener syndrome is a subset of this disorder (1:40,000 males) that presents with the triad of chronic sinusitis, bronchiectasis, and situs inversus. Most immotile cilia cases are diagnosed in childhood with respiratory and sinus difficulties. Cilia present in the retina and ear may also be defective and lead to retinitis pigmentosa and deafness in Usher's syndrome. Men with immotile cilia characteristically have nonmotile but viable sperm in normal numbers. The diagnosis can only be confirmed with electron microscopy of sperm.
Autoimmune infertility has been implicated as a cause of infertility in 10% of infertile couples. The testis is an immunologically privileged site, probably owing to the blood–testis barrier, which consists of Sertoli cell tight junctions and locally downregulated cellular immunity. Autoimmune infertility may result from an abnormal exposure to sperm antigens as the result of vasectomy, testis torsion, or biopsy, which then incites a pathologic immune response. Antibodies may disturb sperm transport or disrupt sperm–egg interaction. Many assays are available to detect ASAs, but assays that detect sperm-bound, and not serum, antibodies are the most clinically relevant.
The agents most commonly responsible for male genital tract infections are listed in Table 44–10. Various products of activated leukocytes can exist in infected semen. A correlation exists between leukocytes in semen and the generation of superoxide anions, hydrogen peroxide, and hydroxyl radicals (reactive oxygen species), all of which can damage sperm membranes. Sperm are highly susceptible to the effects of oxidative stress because they possess little cytoplasm and therefore little antioxidant activity. Damage to sperm from oxidative stress has been correlated to loss of function and damaged DNA. Although genital tract infection has been linked to infertility in epidemiologic studies, the correlation between individual organisms and infertility is unclear. Uncontrolled studies suggest that pregnancy rates may improve after treatment, but controlled studies do not confirm these findings.
Sexual dysfunction stemming from low libido or impotence is a frequent cause of infertility. The male hormonal evaluation can detect organic reasons for such problems. Most cases of situational impotence, in which the stress of attempting to conceive results in poor erections, are treated with sexual counseling and oral phosphodiesterase inhibitors.
Anatomic problems like hypospadias can cause inappropriate placement of the seminal coagulum too distant from the cervix and result in infertility.
Simple problems of coital timing and frequency can be corrected by a review of the couple's sexual habits. An appropriate frequency of intercourse is every two days, performed within the periovulatory period, the window of time surrounding ovulation when egg fertilization is possible. Charting of basal body temperature by the female partner allows for the calculation of that period for the next ovulatory cycle. Home kits that detect the LH surge in the urine before ovulation are also helpful. Couples should be counseled to avoid lubricants if at all possible. It is also wise to discontinue any unnecessary medications during attempts to conceive. Other coital toxins include heat exposure from regular saunas, hot saunas, hot tubs, or Jacuzzis and the use of cigarettes, cocaine, marijuana, and excessive alcohol.