The male reproductive system consists of several structures; two of these structures, the testes and seminiferous tubules, produce the primary male hormones. The testes, a pair of oval glands located in the scrotal sac, are the male gonads. The testes produce male sex hormones. The seminiferous tubules, which are channels in the testes, are the site of spermatogenesis, which is the process by which mature sperm cells are produced.

Androgens are the group of male sex hormones (primarily testosterone) that mediate the normal development and maintenance of the primary and secondary male sex characteristics. Secondary male sex characteristics include advanced development of the prostate, seminal vesicles (two glands adjacent to the prostate), penis, and scrotum, as well as male hair distribution, laryngeal enlargement, thickening of the vocal cords, and male body musculature and fat distribution. Androgens must be secreted in adequate amounts for these characteristics to appear. The most important androgen is testosterone, which is produced from clusters of interstitial cells located between the seminiferous tubules. Besides having androgenic activity, testosterone is also involved in the development of bone and muscle tissue; inhibition of protein catabolism (metabolic breakdown); and retention of nitrogen, phosphorus, potassium, and sodium. These functions contribute to its anabolic activity. The hormone initiates the synthesis of specific proteins needed for androgenic and anabolic activity by binding to chromatin (strands of deoxyribonucleic acid [DNA]) in the nuclei of interstitial cells. In addition, testosterone appears to have an erythropoietic effect in that it stimulates the production of red blood cells (see Chapter 54).

Pharmacology Overview

Androgens and Other Drugs Pertaining to Men’s Health

Testosterone deficiency is treated with exogenous testosterone. There are several synthetic derivatives of testosterone that have improved pharmacokinetic and pharmacodynamic characteristics over the naturally occurring hormone. This is accomplished by combining various esters with testosterone, which prolongs the duration of action of the hormone. For example, testosterone propionate is formulated as an oily solution, and its hormonal effects last for 2 to 3 days; the effects of testosterone cypionate and testosterone enanthate in oil last for up to 2 to 4 weeks. Orally administered testosterone has very poor absorption, because most of the dose is metabolized and destroyed by the liver before it can reach the circulation (first-pass effect; see Chapter 2). To circumvent this problem, researchers developed methyltestosterone (Android) and fluoxymesterone (Halotestin). Both are synthetic dosage forms (tablets or capsules) designed to be effective following oral administration. Methyltestosterone is also available in a buccal tablet, which is dissolved in the buccal cavity (the space in the mouth between the cheek and teeth) and in an injectable form. Transdermal dosage forms of testosterone, including skin patches and a gel, have provided another way to circumvent the first-pass effect that occurs with oral administration of this hormone.

There are other chemical derivatives of testosterone known as anabolic steroids. These are synthetic drugs that closely resemble the natural hormone but possess high anabolic activity. Currently three anabolic steroid drug products are commercially available. These include oxymetholone (Anadrol-50), oxandrolone (Oxandrin), and nandrolone (Deca-Durabolin). Approved indications include anemia, hereditary angioedema, and metastatic breast cancer. Unlabeled (non–FDA-approved) uses for oxandrolone include treatment of human immunodeficiency virus (HIV)–associated wasting syndrome (debilitation related to disease-induced nutritional malabsorption) and alcoholic hepatitis. Oxandrolone is also used in hospitalized patients to stimulate weight gain. Anabolic steroids have a great potential for misuse by athletes, especially bodybuilders and weight lifters, because of their muscle-building properties. Improper use of these substances can have many serious consequences, such as sterility, cardiovascular diseases, and even liver cancer. For this reason, anabolic steroids are currently classified as Schedule III controlled substances by the U.S. Drug Enforcement Administration. This classification implies that misuse of these drugs can lead to psychological or physical dependence or both.

Another synthetic androgen is danazol (Danocrine). Its labeled uses include treatment of hereditary angioedema, and, in women, endometriosis and fibrocystic breast disease.

Mechanism of Action and Drug Effects

The natural and synthetic androgens and the synthetic anabolic steroids have effects similar to those of the endogenous androgens. These include stimulation of the normal growth and development of the male sex organs (primary sex characteristics) and development and maintenance of the secondary sex characteristics. Androgens stimulate the synthesis of ribonucleic acid (RNA) at the cellular level, thereby promoting cellular growth and reproduction. They also retard the breakdown of amino acids. These properties contribute to an increased synthesis of body proteins, which aids in the formation and maintenance of muscle tissue. Another potent anabolic effect of androgens is the retention of nitrogen, also essential for protein synthesis. Nitrogen also promotes the storage of inorganic phosphorus, sulfate, sodium, and potassium, all of which have important metabolic roles, including protein synthesis, nerve impulse conduction, and muscular contractions. All of these effects result in weight gain and an increase in muscular strength. Finally, androgens also stimulate the production of erythropoietin by the kidney, which leads to enhanced erythropoiesis (red blood cell synthesis; see Chapter 54). However, the administration of exogenous androgens causes the release of endogenous testosterone to be inhibited as a result of the feedback inhibition of pituitary luteinizing hormone. Large doses of exogenous androgens may also suppress sperm production as a result of the feedback inhibition of pituitary follicle-stimulating hormone, which leads to infertility.

Androgen inhibitors block the effects of naturally occurring (endogenous) androgens. This is accomplished via inhibition of a specific enzyme, 5-alpha reductase. For this reason, these drugs are also called 5-alpha reductase inhibitors. For unknown reasons, normal male physiology often results in an enlargement of the prostate known as benign prostatic hyperplasia (BPH). This process begins as early as 30 years of age and is present in at least 85% of men by 80 years of age. The most troubling symptom is usually varying degrees of obstructed urinary outflow. Although surgical treatment by transurethral resection of the prostate (TURP) is a common strategy, BPH is also often treatable with a 5-alpha reductase inhibitor. There are currently two such drugs: finasteride and dutasteride. Finasteride (Proscar), the prototypical drug for this class, works by inhibiting this enzyme, which normally converts testosterone to 5-alpha dihydrotestosterone (DHT). DHT is a more potent type of testosterone and is the principal androgen responsible for stimulating prostatic growth, as well as the expression of other male primary and secondary sex characteristics. Finasteride can dramatically lower the prostatic DHT concentrations, which helps to reduce the size of the prostate to ease the passage of urine. Fortunately, finasteride does not cause antiandrogen adverse effects that might be expected, such as loss of muscle strength, and fertility.

The effects of finasteride are limited primarily to the prostate, but this drug may also affect 5-alpha reductase–dependent processes elsewhere in the body, such as in the hair follicles, skin, and liver. Research has demonstrated that the pharmacologic inhibition of 5-alpha reductase prevents the thinning of hair caused by increased levels of DHT. It has been noted that men taking finasteride experience increased hair growth. Therefore, finasteride is also indicated for the treatment of male-pattern baldness as Propecia. Finasteride is indicated for the treatment of baldness only in men, not in women. Finasteride can be teratogenic in pregnant women, and its use in women of any age (pregnant or not) is not recommended. Women need to wear gloves when handling finasteride. Another medication, minoxidil (Rogaine), can be used topically to treat baldness in both men and women. It is discussed in more detail in Chapter 56.

Another class of drugs that may be used to help alleviate the symptoms of obstruction due to BPH are the alpha₁-adrenergic blockers. These drugs are discussed in greater detail in Chapter 19. The alpha₁-adrenergic blockers that are most commonly used for symptomatic relief of obstruction secondary to BPH are terazosin (Hytrin), doxazosin (Cardura), tamsulosin (Flomax), alfuzosin (Uroxatral), and silodosin (Rapaflo). Tamsulosin, alfuzosin, and silodosin appear to have a greater specificity for the alpha₁-receptors in the prostate and thus may cause less hypotension. These drugs have clinical effects of prostate shrinkage immediately, as opposed to the 5-alpha reductase inhibitors, which may take up to 6 months of continual therapy.

There are also two other classes of androgen inhibitors. The first includes the androgen receptor blockers flutamide (Eulexin), nilutamide (Nilandron), and bicalutamide (Casodex). These drugs work by blocking the activity of androgen hormones at the level of the receptors in target tissues (e.g., prostate). For this reason, these drugs are used in the treatment of prostate cancer (see Chapter 46). The second class is the gonadotropin-releasing hormone (Gn-RH) analogues, including leuprolide (Lupron), goserelin (Zoladex), and triptorelin (Trelstar). These drugs work by inhibiting the secretion of pituitary gonadotropin, which eventually leads to a decrease in testosterone production. Both androgen receptor blockers and Gn-RH analogues are used most commonly to treat prostate cancer and are discussed in further detail in Chapter 46.

PATIENT-CENTERED CARE: CULTURAL IMPLICATIONS

Men’s Health Concerns: Prostate Cancer and Its Occurrence and Mortality

It is estimated that 217,730 men will be diagnosed in 2010 with prostate cancer and 32,050 will die of the cancer. During the years 2004 to 2008, the median age at diagnosis for prostate cancer was 67 years of age. Incidence rates by race per 100,000 men are as follows (from cases diagnosed from 2004 to 2008): 156 per 100,000 for all races, 149.5 for whites, 233.8 for African Americans, 88.3 for Asians and Pacific Islanders, 75.3 for Native Americans and Alaska Natives, and 107.4 per 100,000 for Hispanics. Prostate cancer is the most common nonskin malignancy in men and the second leading cause of cancer-related death in men in the United States. African-American men have a higher incidence and at least double the mortality rates as compared with men from other racial ethnic groups.

Data from Howlader N, Noone AM, Krapcho M, et al, editors: SEER cancer statistics review, 1975-2008, Bethesda, MD, 2011, National Cancer Institute, available at http://seer.cancer.gov/csr/1975_2008/. Accessed May 25, 2011; National Cancer Institute at the National Institutes of Health: Prostate cancer, available at www.cancer.gov/cancertopics/types/prostate. Accessed May 25, 2011.

Phosphodiesterase inhibitors are used in the treatment of erectile dysfunction. Sildenafil (Viagra) was the first oral drug approved for the treatment of erectile dysfunction. Sildenafil works by inhibiting the action of the enzyme phosphodiesterase. This in turn allows the buildup in the penis of the chemical cyclic guanosine monophosphate, which causes relaxation of the smooth muscle in the corpora cavernosa (erectile tubes) of the penis and permits the inflow of blood. Nitric oxide is also released inside the corpora cavernosa during sexual stimulation and contributes to the erectile effect. Two drugs that are similar but have a longer duration of action are vardenafil (Levitra) and tadalafil (Cialis). Collectively, these drugs are referred to as erectile dysfunction drugs. Sildenafil is also used to treat pulmonary hypertension (see Chapter 22) under the trade name Revatio.

A second type of drug used to treat erectile dysfunction is the prostaglandin alprostadil (Caverject). This drug must be given by injecting it directly into the erectile tissue of the penis or pushing a suppository form of the drug into the urethra.

A list of all of the men’s health drugs mentioned in the chapter appears in Box 35-1. More information on selected drugs can be found in the Drug Profiles section.

PATIENT-CENTERED CARE: LIFESPAN CONSIDERATIONS FOR THE ELDERLY PATIENT

Sildenafil: Use and Concerns