Chapter 19: Male Genital Tract

The penis, testes, epididymis, vas deferens, seminal vesicles, and the prostate comprise the male genital tract. Circulating markers have been identified for prostate cancer and testicular cancer. For that reason, a discussion of these tumors and their serum markers is presented in this chapter (Table 19–1). Also, laboratory tests are often used in evaluating men with gonadal dysfunction and men who may be subfertile, infertile, or sterile. A summary of these tests and their usage is also provided. The male genital tract is the site of many infectious diseases, a significant proportion of which are sexually transmitted. These are discussed in Chapter 5.

Description

Prostate cancer is a common malignancy of men that increases in incidence with age. It is second only to nonmelanoma skin cancer as the most commonly diagnosed cancer in men (over 150 cases/100,000 men), and second only to lung cancer as the most common cause of cancer death in males. However, most cases are slowly progressive and do not cause major morbidity or lead to death. A major unresolved challenge is differentiating the rapidly progressive and fatal form of prostate cancer from the indolent forms that do not cause death. Mortality associated with the disease has been decreasing. This has been attributed by some to early detection, although a systematic review of published studies has shown no consistent difference in prostate cancer mortality between those who have and those who have not been screened for the disease. The use of laboratory assays to measure the serum prostate-specific antigen (PSA) concentration, however, has had the greatest impact on increased detection of this cancer.

Prostate-specific Antigen

PSA is a serine protease enzyme (also called human kallikrein 3) synthesized almost exclusively by the prostate and secreted into the seminal fluid. A small amount is also found in the blood. In the blood, PSA is largely bound to enzyme inhibitor proteins such as alpha₁-antichymotrypsin and alpha₂-macroglobulin. A small fraction of circulating PSA is free (unbound).

PSA levels in blood generally correlate with the size of the prostate. The larger the gland, the higher the PSA value. PSA may also increase transiently after a vigorous rectal examination, and after prostate biopsy or surgery. Inflammation and infarction of the prostate can also cause increased PSA, which returns to normal gradually. It is therefore recommended that elevated PSA levels should be confirmed by repeat measurement (at least 2-3 months apart) before any other action is taken, to exclude 1 of these insignificant causes of high PSA.

Prostate disease is common in men after the age of 50 years, and by age 70 years the majority of men have prostate disease. The 2 major diseases of the aging prostate are prostate carcinoma and benign prostatic hyperplasia (BPH). A number of factors have been evaluated to try to distinguish between these causes of increased prostate size and/or increased PSA levels. Both prostate cancer and BPH contribute to elevations in serum PSA.

In most laboratories, the PSA threshold considered positive for cancer screening is >4 ng/mL; above that threshold concentration, the positive predictive value for prostate cancer (the likelihood that cancer will be found in a biopsied prostate gland) is about 30%. In general, PSA is increased to a greater extent in prostate cancer than in BPH; PSA is rarely >20 ng/mL in BPH, and in only about 10% of cases is it >10 ng/mL, so higher values suggest cancer. A high PSA in a man with a small prostate gland on rectal examination is more worrisome for cancer than a similar PSA value in a person with a very large gland. The ratio of free PSA/total PSA may be a better diagnostic marker for prostate cancer than total PSA; in general, a lower proportion of free PSA is found in patients with prostate cancer, but there is a wide overlap in values.

PSA has been used for several purposes related to prostate cancer: screening (testing in persons without symptoms or signs of disease), prediction of the course of disease, prediction of the stage of disease, and follow-up after treatment. The most controversial use of PSA measurements is in screening. Two large randomized trials have been published with long-term outcomes of prostate cancer screening. The US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial showed no effect on cancer-specific or all-cause mortality after 10 years. The European Randomized Study of Screening for Prostate Cancer found that screening was associated with reduced cancer-specific mortality in men aged 55 to 69 years after 9 years of follow-up; to prevent 1 cancer death, 1400 men would need to be screened and 48 treated.

Because of the side effects of diagnostic biopsy and complications of treatment of prostate cancer and the minimal, if any, survival benefit from prostate cancer screening, in 2012, the US Preventive Services Task Force recommended that men not be screened for prostate cancer. Guidelines for prostate cancer screening from other professional groups, including the American Urological Association (AUA) and the American College of Physicians (ACP), recommend individual decision making with information provided to the patient about both potential risks and benefits, and that screening might be reasonably offered to men between ages 50 (for the ACP) or 55 (for the AUA) and 69.

It should be noted that PSA is not highly sensitive for detecting cancer. It is estimated that only about 50% to 60% of those with localized and potentially curable cancer have increased PSA, and recent studies have found that many patients with less well-differentiated prostate cancers actually have PSA values as low as 1 ng/mL.

Limited evidence suggests that the rate of rise in PSA can predict more aggressive cancers. A review of published studies found that men with more rapid rises in PSA (a rise >0.35 ng/mL per year, 10 years before a definitive diagnosis, or a rise >2 ng/mL in the year before a definitive diagnosis) were far more likely to have recurrence after surgery and to die from cancer than those with more slowly rising PSA. In men who have decided to not have surgery, the rate of rise of PSA was also found to be predictive; if the PSA doubling time was less than 3 years, the likelihood of locally progressive disease was high, while it was very low for those whose PSA increased less than 2-fold over 10 years. More studies will be needed to confirm these findings and to determine whether this information can be useful in determining treatment.

PSA measurement is of some use in the initial staging of a patient with prostate cancer. In general, the higher the PSA, the less likely that cancer is localized to the prostate and the more likely that it has spread. Distant metastases are rare in persons with PSA <20 ng/mL, so performance of imaging studies of bone (the most common site of metastasis) for preoperative staging of cancer has little benefit in those with lower PSA values.

The most widely accepted use of PSA is to monitor patients after treatment. Since about 99% of prostate cancers produce PSA, and since PSA is made almost solely in the prostate, successful surgical removal of the gland (and cancer) should result in a serum PSA less than 0.1 ng/mL by 3 months after surgery. Failure of PSA to become undetectable indicates residual cancer that was not removed by surgery. With recurrence of cancer, PSA levels increase up to a year and a half before clinical evidence of recurrent cancer, allowing treatment of persons with rising PSA before their clinical condition deteriorates. With radiation therapy, PSA typically will fall to normal (usually to <1 ng/mL by 1 year after completion of radiation) with successful treatment, but will usually not be undetectable. Because prostate cancer responds to androgens, removal of the testes and the use of drugs that block androgen production are widely used to treat metastatic prostate cancer. The production of PSA is androgen dependent. Rarely, PSA levels will fall dramatically with androgen deprivation even though there is little or no change in the amount of tumor. In most cases, though, PSA is a reliable marker of tumor response to androgen deprivation as a treatment for prostate cancer.

Description

The 2 major categories of testicular tumors are germ cell tumors (which include seminomas and nonseminomatous germ cell tumors [NSGCT]) and sex cord or stromal tumors (mainly Leydig cell and Sertoli cell tumors). Seminomas and NSGCT comprise more than 90% of testicular cancers. Most persons with germ cell tumors have a mixture of histologic varieties. Testicular germ cell tumors have a peak incidence in 15- to 34-year-old males, and are the most common type of tumor found in men of that age group. Testicular cancer is most commonly identified by finding an enlarged testicle during a routine physical or by a man on self-examination. If an ultrasound examination confirms the presence of an intratesticular mass, surgery is usually performed quickly to remove the testicle, its adnexa, and a long segment of the spermatic cord (radical orchiectomy). The diagnosis of testicular cancer, like most other cancers, is made by histopathologic examination of the testicle.

Diagnosis

Germ cell tumors often produce substances that can be used as tumor markers to evaluate the patient for complete removal of the tumor, detect recurrent cancer, and monitor treatment for any residual or recurrent tumor. The 3 important serum tumor markers for testicular cancers are human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), and lactate dehydrogenase (LD). LD elevation, while present in about 50% of seminomas and 10% of NSGCT, is not specific, since damage to muscle, liver, cardiac, and other tissue damage can raise LD levels in the blood. Elevation of the LD-1 isoenzyme is characteristic of testicular tumors, but LD-1 is also elevated after myocardial infarction. Seminoma is associated with increased levels of hCG, but the increased levels are seen in only about 15% of seminoma cases. Pure seminomas do not produce AFP, but mixed tumors that contain predominantly seminomatous components may produce AFP. In NSGCT, approximately 85% to 90% of cases have at least 1 of the 3 tumor markers elevated. Yolk sac tumors produce AFP, a normal product of the fetal liver and yolk sac, in about 90% of cases. Choriocarcinoma, a malignant tumor resembling the placental cells, produces hCG in close to 100% of cases. As is generally true for circulating tumor markers, they are most useful for monitoring recurrence of disease or as a measure of response to therapy. Neither hCG nor AFP is useful in screening patients for testicular tumors, and they have a limited but helpful role in establishing the diagnosis. Higher levels of hCG and LD-1 at the time of diagnosis are associated with more aggressive cancers and, overall, a less favorable outcome, and are therefore included in staging classifications for testicular cancer cases. In order to determine whether a testicular tumor is associated with elevated tumor marker levels, it is recommended that baseline levels of these 3 markers be measured prior to surgery, since levels may fall quickly after surgery.

hCG, LD, and AFP are significantly affected by diseases in other organs. LD is found in all cells. Therefore, damage to any cell can cause increased LD. Since red blood cells contain LD, a sample collected for LD measurement in which there is red blood cell hemolysis will show an elevated LD, with much of the LD originating from red blood cells. This is also particularly problematic in the setting of chemotherapy, where transient LD increases occur from the cell damage expected from chemotherapy treatment. AFP is also produced by hepatocytes, as discussed in Chapter 16. Injury to the liver, as occurs with acute or chronic hepatitis, also commonly causes mild-to-moderate increases in AFP that can lead to suspicion of recurrent testicular carcinoma.

Description

While complete gonadal failure in men is rare (and is discussed more fully in Chapter 22), partial androgen deficiency is common with advancing age in men. This has also sometimes been referred to as “andropause,” and considered by some to be analogous to menopause, the age-related gonadal failure in women. There are a number of differences between age-related declines in gonadal function in men and women, however. While gonadal failure is inevitable in women, not all men develop low levels of testosterone. Menopause typically occurs between the mid-40s and mid-50s, whereas relative androgen deficiency develops over a much broader age range in men. Estrogen and progesterone levels fall to extremely low levels in women and are accompanied by high gonadotropin (FSH and LH) levels. However, partial androgen deficiency in men is associated with mildly decreased testosterone levels and is usually not associated with abnormally high gonadotropin levels. According to the Endocrine Society consensus guidelines based on testosterone levels in a reference population of healthy young men, only 7% of men in their 40s have low androgen levels. However, the figure rises to 30% of men in their 50s, almost half of men in their 60s, and to 90% of men in their 80s. Current guidelines indicate that the reference (“normal”) range of testosterone should be based on the values found in healthy young men, despite some concerns that classifying such a large proportion of testosterone values seen in older men as abnormal might encourage inappropriate or unneeded supplemental androgen therapy.

As in women, routine use of hormone replacement in men is controversial. Androgens increase muscle and bone mass, and may protect against falls and bone fractures. Androgen deficiency can cause mood changes and sexual dysfunction, both of which may respond to androgen treatment. On the negative side, however, androgens are involved in the pathogenesis of both BPH and prostate cancer, may lead to a fall in sperm count, and cause undesirable changes in blood lipids, which may increase the risk of myocardial infarction and stroke. Limited data on safety and effectiveness of androgen replacement are available, and some level of efficacy that had been anticipated has not been shown in controlled trials. For example, administration of testosterone together with sildenafil was not better than sildenafil alone in improving erectile dysfunction in 1 study. Whereas treatment of hypogonadism in young men with primary gonadal failure is beneficial, clear clinical benefits of testosterone therapy in men aged 65 and above with age-related decreases in testosterone levels have not been demonstrated in randomized trials. Long-term effects of testosterone therapy on the risk of prostate-related and cardiovascular-related adverse events remain unknown.

Diagnosis

Laboratory testing for partial androgen deficiency generally begins with measurement of serum testosterone. Normal levels are often stated to be greater than 250 to 350 ng/dL. Androgen deficiency is unlikely to be present if the total testosterone is >400 ng/dL. A problem with evaluation of total testosterone levels is that changes in the level of testosterone-binding proteins are common. Free testosterone, not bound to proteins, contributes significantly more to the biological effects of testosterone than does protein-bound testosterone. However, it is widely believed that testosterone bound to albumin (about 40% of total) may contribute partially to the biological effects of testosterone. The major testosterone-binding protein, sex hormone-binding globulin (SHBG), is increased by androgen deficiency, but decreased by obesity, both common problems in older men. Ideally, free testosterone is quantitated, but some assays for measurement of free testosterone are unreliable. This has led to the use of tests to determine “bioavailable testosterone,” which are most helpful in those with testosterone levels between 200 and 400 ng/dL.

Transient decreases in testosterone and gonadotropin levels are commonly seen in persons who are acutely ill. Testing of gonadal function should be avoided in hospitalized individuals for that reason. Certain medications, as well as opiates and ethanol, can cause transient decreases as well. Testosterone secretion has a circadian rhythm, with higher levels in the morning, and lower concentrations in the afternoon and evening. The reference ranges for expected values of testosterone are generally based on morning samples. If treatment decisions are to be based on androgen concentrations, testosterone blood tests should be drawn in the morning, and fasting is not required. Since testosterone serum levels within an individual are variable, low concentrations should be confirmed by repeat testing before initiating therapy.

In young men with low testosterone, guidelines suggest measurement of LH. Generally, FSH follows LH and does not add additional information. It is expected that LH levels are usually within the reference range in age-related partial androgen deficiency. Very low levels of LH suggest a pituitary or hypothalamic problem, and require further evaluation of pituitary function, while high levels of LH suggest other causes of a low androgen level.

Description

Infertility (defined as a failure to conceive after 1 year of unprotected intercourse) affects about 15% of couples attempting a pregnancy, and most experts agree that male infertility (alone or in combination with female infertility) accounts for about half of these cases. The causes of male infertility range from congenital absence of the vas deferens or incomplete spermatogenesis to subtle pathologies of sperm shape and function. In contrast, female infertility is usually caused by tubal blockage, uterine or endometrial abnormalities, or abnormal levels of reproductive hormones. Female infertility is relatively easily diagnosed by hormone assays, menstrual cycle analysis, and radiologic studies. The male partner in an infertile couple is often overlooked or incompletely evaluated, even though male factors may be a major contributing factor. Endocrine abnormalities (eg, isolated androgen deficiency) are exceedingly rare (about 1%) among males of infertile couples. Since subtle sperm dysfunctions not obvious by microscopic semen analysis may preclude fertilization, a normal semen analysis (SA) is not necessarily predictive of fertility. In fact, a complete lack of sperm in semen (azoospermia) is the only highly predictive finding for infertility by SA.

Absence of spermatozoa in the semen may be caused by either failure of the testes to produce sperm (ie, male sterility) or a blockage of the excurrent ducts of the male genital tract. The former is nonobstructive azoospermia (NOA), and the latter, obstructive azoospermia (OA). When azoospermia is discovered by SA, a medical history and physical examination by a qualified physician is recommended. Testicular biopsy may also be performed to differentiate NOA from OA. OA may be congenital or acquired. Vasectomy is usually an elective minor surgery leading to azoospermia for contraception, but the vas or epididymis also may become unknowingly blocked after a sexually transmitted infection. Azoospermia may persist after vasectomy reversal. Congenital bilateral absence of the vas deferens (CBAVD) is found in men carrying one of the many cystic fibrosis alleles, as well as in men with clinically apparent cystic fibrosis. In all these cases of OA, spermatozoa are almost always able to be retrieved from the testis by a urologic surgeon. Testicular sperm are not capable of fertilization except by intracytoplasmic sperm injection, in which individual sperm are microinjected into an oocyte in an in vitro fertilization (IVF) laboratory. In the case of a cystic fibrosis carrier, the partner should be checked to determine if she is also a carrier for cystic fibrosis so that the couple understands their risk to conceive a child.

Absence of the vasa deferentia may be determined by palpation on physical exam, and may be suggested by absence of fructose in the semen. Fructose is made exclusively in the seminal vesicles, and these glands contribute about 60% of the semen volume. Since they are embryonic outgrowths of the vasa deferentia, they are usually absent in men with CBAVD.

Two reasons for NOA are absence of germ cells in the testis (Sertoli-only syndrome) and failure of spermatogenesis (only mitotic cells or no late stages of sperm production). These conditions may be genetic, due to failure of primordial germ cells to migrate to the testis, or acquired through exposure to toxicants. In addition, microdeletions in the Y chromosome in specific regions are associated with NOA or severe oligozoospermia. Testosterone or androgen therapy (see above) for low testosterone or bodybuilding will often result in azoospermia or oligozoospermia due to inhibition of the hypothalamic–pituitary axis, decreased LH, and subsequent lowering of the high intratesticular:plasma ratio of testosterone required for sperm production. Men with testicular and other cancers may exhibit NOA or oligozoospermia. Conversely, men with NOA or oligozoospermia are at increased risk for later development of testicular cancer.

Spermatozoa may not be entirely missing in NOA. A few stem cells throughout the testis may be present, although a random biopsy may not detect any. In such cases, exceedingly low numbers of sperm may be present in the semen, possibly on a cyclical basis. Cryptozoospermia is the presence of very rare sperm in the semen. Often, high levels of FSH are associated with NOA, due to dysfunctional Sertoli cells and lack of the Sertoli hormone inhibin. However, high FSH has not proven to be a good indicator of the absolute absence of spermatogenesis. The surgical technique known as microsurgical testicular sperm extraction has proven to be useful in these cases. Under the surgical microscope, a few seminiferous tubules might be located that have complete spermatogenesis. Highly trained staff in the andrology or embryology laboratory are needed to identify and recover sperm from the testis in these cases.

In other cases of male infertility, sperm will be present in the semen. The human, unlike almost any other species, produces spermatozoa with numerous defects. “Normal” values for human SA are both surprisingly poorly established and highly variable from 1 ejaculate to another, and between different men. Although a typical ejaculate contains 200 to 300 million sperm, fertilization only takes 1, and at the time of fertilization there are only about a dozen sperm associated with the egg. If only 1% of sperm are functionally and structurally normal, then the typical ejaculate will contain about 2 to 3 million of these “good sperm.” Apparently this is enough to help propagate the human population. SA helps identify men who have a few “good sperm,” and diagnose specific sperm problems that may permit therapy or advanced reproductive techniques, or help guide decisions by the couple.

Diagnosis and Laboratory Test Interpretation

SA is the cornerstone of male infertility diagnosis, and should be performed early in the evaluation of the infertile couple. Collection of a semen sample should take place after 2 to 5 days of sexual abstinence. Longer abstinence is associated with lower motility and higher leukocyte counts, and shorter periods usually lead to lower volumes and sperm counts. A sterile plastic container, known not to be toxic to sperm, is required. Usually a sterile urine collection cup is satisfactory. If the sample is not collected in a special collection room near the lab, it should be transported in a tightly sealed collection cup in a sealed plastic bag, protected from light, heat, and cold. A temperature between room temperature and body temperature is adequate. Seminal fluid characteristics are measured after allowing semen to liquefy (due to the enzymatic action of PSA) for 15 to 30 minutes at 37°C or at room temperature. Analysis should be completed within 60 minutes after ejaculation. In vivo, sperm typically swim out of semen into the cervical mucus within a half hour. Semen may contain hepatitis, HIV, and other pathogens. Basic precautions for handling potentially infectious body fluids must be followed.

The main tests in SA are ejaculate volume, sperm count, sperm motility, sperm morphology, and leukocyte count. Aside from azoospermia, findings that may contribute to a couple's infertility include low sperm concentration or total number of sperm (oligozoospermia), poor sperm motility (asthenozoospermia), very poor sperm morphology (teratozoospermia), or any combination of the 3. Additionally, a high number of neutrophils or macrophages in the semen (leukocytospermia) may affect sperm function by inducing oxidative stress through the generation of reactive oxygen species. Leukocytes are likely present in all semen samples. There is lack of consensus on the number that is considered abnormal, with authorities suggesting various cutoffs from 200,000 to 1 million per mL of semen.

A semen fructose analysis may be considered if there is unexpected azoospermia. Sperm viability is important to determine when motility is very low. Sperm agglutination and the presence of antisperm antibodies may indicate an immunologic basis for infertility. These highly specialized tests typically are performed in laboratories certified specifically for SA.

Interpretation of sperm morphology is controversial, largely because of a lack of supporting data relating sperm morphology to fertility. Very few human sperm are “perfect”; in fact, if at least 4% of sperm have normal morphology, then the specimen morphology is generally considered to be normal. The clinical significance of sperm morphology is best understood when most of the sperm have specific defects. The absence of acrosomes (the specialized structure at the tip of the sperm head) is associated with inability to fertilize eggs, and, sometimes, inability to activate oocytes to complete meiosis. Abnormal midpieces or tails may be associated with poor motility.

If SA is abnormal, it should be repeated after at least 1 month. SA parameters can vary substantially within an individual. Therefore, a single abnormal specimen should not be used to establish a diagnosis.