Shehzad Basaria
Disorders of the male reproductive system are common. For example, approximately 1 in 500 males is born with Klinefelter syndrome, a condition associated with low testosterone levels and infertility. More importantly, nearly 50% of men experience some degree of erectile dysfunction between the ages of 20 and 50 years (1). It is important for primary care clinicians to be able to identify and treat (or refer) such patients. Although androgen deficiency is not life threatening, it may have devastating effects on psychological, sexual, and somatic health in men. It is therefore important that clinicians have adequate knowledge about the diagnosis and treatment of reproductive and sexual disorders in men and be able to distinguish patients who only require reassurance from those who need additional evaluation and treatment or who should be referred to a specialist for more complex testing or therapy.
Male Reproductive Physiology
Male Sexual Differentiation
Genetic sex is determined at conception when an egg bearing an X chromosome is fertilized by a sperm bearing either a Y or an X chromosome, resulting in an XY (male) or an XX (female), respectively. The gonadal sex (i.e., the differentiation of testes or ovaries) is determined at the beginning of the 8th week of gestation. The short arm of the Y chromosome contains the “sex-determining region” that causes the gonad to differentiate into a testis. The embryonic testes produce two critical molecules, testosterone and the müllerian-inhibiting factor (MIF). Testosterone is the major male sex steroid and is responsible for the development of the undifferentiated external genitalia into a penis and scrotum and of the internal wolffian duct system
P.1454
into epididymis, vas deferens, prostate, and seminal vesicles. Dihydrotestosterone (DHT), a testosterone metabolite, is primarily responsible for the development of external genitalia. Hence, in the absence of the production (or action) of testosterone, female external genitalia (labia and clitoris) form. MIF is a peptide that mediates the regression of the primitive müllerian duct structures in the 6th week of gestation. In the absence of MIF, the müllerian ducts develop into a vagina, uterus, and fallopian tubes. Even in the absence of both ovaries and testes, normal female genitalia can develop. The appearance of the external genitalia identifies an individual's apparent gender at birth. Further sexual development occurs at puberty as a result of greatly increased secretion by the gonads of sex steroid hormones. In males, growth of male pattern body and pubic hair, beard, increase in muscle mass, deepening of voice, and onset of male libido with increased frequency of erections and ejaculations, are characteristic effects of testosterone. In females, rounding of body contours with breast growth and subcutaneous deposition of fat in the hips and buttocks, and also the onset of menses, are effects of cyclic estrogen secretion, whereas growth of pubic and axillary hair (and probably libido) are manifestations of adrenal androgen, and to a lesser extent, ovarian androgen secretion. Both sexes experience a period of accelerated increase in height at puberty (growth spurt), which is followed by closure of the epiphyses and cessation of growth of long bones.
Hypothalamic–Pituitary-Gonadal Axis
The hypothalamus, the pituitary and the testes are the three units forming the hypothalamic–pituitary–gonadal (HPG) axis in men. The neurons in the preoptic area of the hypothalamus secrete a decapeptide, gonadotropin-releasing hormone (GnRH). These neurons are also known as the GnRH pulse generator. Axons from these neurons end on capillaries of the median eminence in the pituitary, into which, at intervals of 60 to 120 minutes, they secrete GnRH. These vessels collect into the pituitary portal veins that ramify as sinusoidal capillaries within the pituitary gland. GnRH reaches the pituitary in high concentrations, where it stimulates gonadotropes to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH acts on the Leydig (interstitial) cells of the testis to stimulate testosterone secretion (2), which will not only be responsible for maintaining male secondary sexual characteristics, but also spermatogenesis. Testosterone, in turn, acts on both the hypothalamus and the pituitary to inhibit GnRH and LH secretion, respectively (Fig. 85.1). A decline in testosterone production as a result of damage to the Leydig cells results in loss of negative feedback and a rise in LH levels. FSH acts on the seminiferous tubules to initiate and maintain spermatogenesis. Therefore, induction of male fertility depends on the presence of FSH. Another target for FSH is the Sertoli cells (supporting cells), which in turn produce androgen binding protein, and a hormone called inhibin.This peptide is responsible for down-regulating pituitary production of FSH, forming a closed-loop negative feedback system (Fig. 85.1). Testosterone secretion follows a diurnal pattern with peak levels occurring around 8 a.m. and nadir around 10 p.m. This rhythm, however, is lost in elderly men (3).
|
FIGURE 85.1. Reproductive endocrinology in the male. A variety of central nervous system inputs, from both exogenous (e.g., environmental stress) and endogenous (e.g., biorhythms) sources, act via neurotransmitters and neuropeptides to influence the amplitude and frequency of pulsatile hypothalamic neuronal output (light gray arrows) of gonadotropin-releasing hormone (GnRH) into the pituitary portal system. GnRH stimulates pituitary gonadotropes to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH induces the Leydig cell (LC) compartment of the testis to secrete testosterone (T). FSH and T act together to stimulate spermatogenesis in the seminiferous tubule compartment (ST). T acts via negative feedback (dark gray arrows) to inhibit gonadotropin and GnRH secretion, probably after aromatization locally to estradiol. Inhibin, produced by the ST in response to FSH, also acts by negative feedback to decrease FSH release. |
Testosterone Metabolites, Transport, and Secretion
Metabolites
Despite being an active hormone itself, testosterone is also a “pro-hormone” because it is metabolized into two biologically active hormones that play an important role in mediating some of its effects on various tissues. These include dihydrotestosterone (DHT) and estradiol (E2) (Fig. 85.2).
DHT
Testosterone is converted to DHT by 5-α reductase. This enzyme has two isoforms (4): type 1, which is expressed in
P.1455
nongenital skin and liver; and, type 2, which is the enzyme of importance since it is expressed in genital skin and the male urogenital tract. It is DHT that is responsible for the development and maturation of the external genitalia and also has a role in male sexual function (5). Congenital deficiency of this enzyme results in children being born with ambiguous genitalia (6). Despite its important role in sexual development, formation of DHT accounts for a fraction of testosterone metabolism. Since there is only one androgen receptor, DHT also acts via this receptor and has a higher affinity for the receptor compared to its parent compound, testosterone.
|
FIGURE 85.2. Metabolites of testosterone and their actions. |
E2
Estradiol, or E2, has long been considered as only a “female” hormone. However, recent studies suggest that it plays an important role in the maintenance of the male skeleton and possibly in male sexual function as well (7,8). Testosterone is converted to E2 by aromatase, an enzyme that is a product of the CYP19 gene. Though ubiquitous, it is mainly concentrated in adipose tissue, the main site of estrogen formation in men. Approximately 80% to 85% of E2 is formed in adipose tissue with the remaining 15% directly secreted by the testes. In men, E2 is responsible for epiphyseal maturation in adolescents (regulating height), regulation of bone mass (in which it is more important than testosterone) (9,10), formation of breast tissue, and for feedback regulation of the HPG axis (E2 is more potent in suppressing gonadotropins as compared to testosterone).
Transport
Testosterone is mainly transported in the plasma bound to proteins. Approximately 44% of testosterone is bound with very high affinity to the sex hormone-binding globulin (SHBG). About 54% is bound with a low affinity (loosely bound) to albumin. This means that only 2% of testosterone circulates freely and is biologically active (free testosterone). However, when needed, the albumin-bound (loosely bound) testosterone dissociates and is readily available to the tissues. Hence, the combination of free testosterone and albumin-bound testosterone is termed bioavailable testosterone (11). SHBG is synthesized in the liver and its levels fluctuate under various circumstances. Estrogen therapy, hyperthyroidism, and male senescence increase SHBG levels while androgen therapy, severe hepatic dysfunction, and hypothyroidism decrease it. Although these changes alter the levels of total testosterone, the HPG unit adjusts to maintain free and bioavailable testosterone levels in the normal range.
Secretion
There are different stages of testosterone secretion.
Stage I
This first stage occurs during fetal life. During the 8th week of gestation, fetal testes begin to secrete testosterone. These levels are maintained until the end of the second trimester and are responsible for fetal androgenization. After that, levels fall at the beginning of the third trimester and remain very low until birth.
Stage II
The second stage of testosterone secretion occurs at birth. Although initial androgen levels are similar in both sexes, shortly after parturition testosterone levels rise in a male infant and remain elevated throughout infancy. Thereafter, levels fall and remain low until the onset of puberty.
Stage III
The third stage of secretion starts at puberty and is responsible for further maturation of sexual organs and development of a male phenotype. Adult levels are achieved by the age of 16 years and are maintained until the fourth decade of life when they begin to decline (see Andropause below). The testes in a normal young man produce 3 to 10 mg of testosterone daily, an amount that translates into normal serum levels of 300 to 1,000 ng/dL (12).
End-Organ Effects of Testosterone
Testosterone acts on many organ systems. It is responsible for anabolic effects on muscle and hypogonadal men have decreased muscle mass and strength, which is improved by testosterone replacement (13). This anabolic effect is directly mediated by testosterone via the androgen receptor, resulting in an increased rate of muscle protein
P.1456
synthesis (14). Similarly, testosterone replacement also reduces fat mass. Hypogonadism of any etiology results in bone loss and predisposes to osteoporosis, a phenomenon that is evident in men with prostate cancer undergoing medical or surgical castration (15). Testosterone replacement results in an improvement in bone mass (16). Estradiol, which is produced by aromatization of testosterone, also has a major role in maintaining bone mass in men. Therefore, the male skeleton benefits from both testosterone and estradiol (7). Testosterone also has a fundamental role in male sexual function. It is responsible for libido (sexual desire), early morning erections, and potency. Patients with hypogonadism present with decreased libido and sexual dysfunction, which are restored by androgen replacement (17). Testosterone also influences cognition. Recent evidence suggests that testosterone replacement in hypogonadal men improves short-term memory, although this effect could be because of its conversion to E2 (18). In addition to testosterone, DHT also has an independent role in sexual function (5).
|
TABLE 85.1 Causes of Primary and Secondary Hypogonadism |
||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||
Male Hypogonadism
As discussed above, testes have two functional compartments: the Leydig cells, which synthesize and secrete testosterone, and the seminiferous tubules, which are responsible for spermatogenesis. Failure in either compartment (i.e., in testosterone or sperm production) is referred to as male hypogonadism. In certain conditions both compartments are affected simultaneously, whereas in others one is affected predominantly. Hypogonadism can be divided broadly into primary (testicular) or secondary (hypothalamic/pituitary) causes. In the former, pituitary gonadotropins are elevated due to loss of negative feedback whereas in the latter, gonadotropins are low or inappropriately normal despite low testosterone. In some rare cases, hypogonadism occurs due to defects in androgen receptors. In these conditions, serum testosterone levels are normal or elevated; however, the body is unable to respond to its action due to mutant receptors. Table 85.1summarizes these conditions.
Etiology
Primary Hypogonadism (Hypergonadotropic Hypogonadism)
The most common genetic cause of primary hypogonadism is Klinefelter syndrome, occurring in 1 in 500 live male births (19). In its classic form, it occurs due to chromosomal nondisjunction producing a 47XXY karyotype. These patients have small, firm testes and gynecomastia. They usually enter puberty but fail to progress fully and present with a “eunuchoid habitus” (see later discussion). They typically have erectile dysfunction, a small phallus, and incomplete masculinization. Testosterone levels are generally low, but may be in the low-normal range in patients with mosaicism (47XXY/46XY). Other genetic causes of primary hypogonadism include deficiency of critical enzymes in the sex steroid synthetic pathway and cryptorchidism. Acquired causes include trauma, testicular torsion, cytotoxic agents (alkylating agents like
P.1457
cyclophosphamide and chlorambucil), radiation damage, infection (mumps orchitis) or infiltrative diseases. Certain other drugs, such as ketoconazole and glucocorticoids, inhibit testosterone production. Autoimmune damage to the testis may occur either alone or as part of autoimmune polyglandular syndrome (Hashimoto thyroiditis, Addison disease, vitiligo, primary hypoparathyroidism, or pernicious anemia). Occasionally, a varicocele may also produce hypogonadism (the proposed mechanism being increased scrotal temperature due to pooling of blood).
Secondary Hypogonadism (Hypogonadotropic Hypogonadism)
Among the genetic causes of secondary hypogonadism, Kallmann syndrome is one of the most common. This syndrome is characterized by hypogonadotropic hypogonadism (because of deficient GnRH secretion), anosmia (or hyposmia), red-green color blindness, midline facial abnormalities, and hearing loss (20). The inheritance is X-linked and is due to deletion of the KAL gene on the short arm of the X chromosome. Distinct from Kallman syndrome is another condition called idiopathic isolated hypogonadotropic hypogonadism. This condition is not accompanied by any of the other features of Kallman syndrome and, except for low gonadotropins, the other pituitary axes are normal. The congenital form of idiopathic isolated hypogonadotropic hypogonadism results in micropenis at birth and failure to reach puberty. There is also an acquired variety of idiopathic isolated hypogonadotropic hypogonadism, which occurs in adulthood in men who have undergone normal puberty and have been fertile, but who later develop hypogonadism (21). Acquired central hypogonadism may be infectious (e.g., tuberculosis hypophysitis), infiltrative (sarcoid), traumatic (deceleration injuries leading to interruption of the pituitary stalk), vascular (pituitary apoplexy) or neoplastic (nonsecreting or functioning macroadenomas compressing the gonadotropes) (see Chapter 81). Hyperprolactinemia (of any etiology) also results in central hypogonadism by inhibiting GnRH synthesis. Many drugs (e.g., glucocorticoids, opioids) and many acute or chronic medical conditions may also inhibit GnRH synthesis. Finally, tumors (lung, lymphoma, renal) that metastasize to the hypothalamus or pituitary may also result in central hypogonadism (22).
Androgen Resistance
Hypogonadism because of androgen resistance is always genetic and is caused by absence or dysfunction of the androgen receptor. It is expressed as a continuum, ranging from complete androgen insensitivity (formerly called “testicular feminization syndrome”), in which the phenotype is female and the affected patients have female breasts and external genitalia at birth and normal estrogenization at puberty, but lack a uterus and hence present with primary amenorrhea through varying degrees of partial androgen sensitivity (Reifenstein syndrome), in which the presentation ranges from abnormalities of midline fusion of labioscrotal structures resulting in gender-assignment confusion at birth to minor defects such as hypospadias and cryptorchidism, in which phenotypic gender is still clearly male. In all these cases, the genetic sex is male (i.e., XY).
Diagnosis
The approach to the patient with symptoms suggestive of hypogonadism should be directed first at determining whether hypogonadism truly exists, then at its classification as discussed earlier, next at discovering its specific cause, and finally at providing appropriate therapy and/or referral for the condition diagnosed. Manifestations of hypogonadism vary with the age at which hypogonadism develops.
In Utero
Absolute testosterone deficiency in the first trimester results in female external genitalia at birth; incomplete deficiency results in genital abnormalities such as hypospadias. When testosterone deficiency occurs in the last trimester of pregnancy, the fetus has normal external genitalia but may have a micropenis. These patients are usually identified at birth and referred to an appropriate specialist, so they rarely present as a diagnostic problem for the clinician whose practice is limited to adults.
Prepubertal
Hypogonadism at this stage is expressed as failure of secondary sex characteristics to appear at an appropriate age. It may stem from almost any of the causes cited previously and must be differentiated from constitutional delayed puberty, which is a common, idiopathic, self-limited, familial condition. A strong family history of late blooming and a finding of testicular enlargement are reassuring in this regard. Benchmarks of pubertal development in adolescent boys are available (see Chapter 11). In general, any boy who reaches 16 years of age without signs of pubertal onset (one of the first changes being an increase in testicular size), or who begins but does not complete puberty by age 18 years, deserves further investigation. The index of suspicion should be heightened if the patient has a history of childhood genital abnormalities (e.g., hypospadias, undescended testes) or signs or symptoms of a disease that can produce hypogonadism (e.g., headaches and/or a visual disturbance suggestive of a pituitary tumor).
P.1458
Postpubertal
The gradual loss of libido, erectile function, and male secondary sex characteristics is a common presentation of hypogonadism at this stage. This may be so insidious that it is taken for granted by the patient, especially in a man progressing from middle age to old age.
History
A proper history should include a chronicle of pubertal progression (i.e., time of pubarche, beard growth, voice change, growth spurts, erections, and ejaculations.) Similarly, loss or diminution of libido, erections or ejaculations, slowing of beard growth, thinning of body and pubic hair, gynecomastia, and loss of aggressive impulse or drive should be evaluated. Severely hypogonadal men may report “hot flashes” similar to those seen in menopausal women. The presence of headaches, double vision, or reduced peripheral vision may give clues to a pituitary tumor. Symptoms of hypothyroidism, adrenal failure, and growth hormone deficiency also indicate pituitary damage. Gynecomastia or galactorrhea indicate hyperprolactinemia. History of urologic problems, cryptorchidism, hypospadias, or orchitis is important. Personal or family history of hemochromatosis suggests iron deposition in the pituitary or testes. Finally, a family history of delayed puberty or of other endocrine abnormalities may suggest either hereditary late blooming or familial autoimmune endocrinopathy.
Physical Examination
The facies should be evaluated first. Does the patient look mature or babyish, masculine or feminine? Secondly, body habitus should be evaluated for “eunuchoid” proportions. This is defined as (a) lower body segment (floor to pubis) more than 2 cm greater than the upper body segment (pubis to crown); and, (b) arm span more than 2 cm greater than the height. These dimensions are equal in normal men. The eunuchoid proportions are seen if hypogonadism occurs before puberty (lack of estrogen results in a delay in fusion of the epiphyses which results in long bones). Appropriate muscle mass, axillary hair, and a palpable prostate on digital rectal examination are evidence against long-standing hypogonadism. Male pattern baldness is also an androgen-dependent process. The presence of acne is also a sign of androgen activity. Eyes should be evaluated for limitation of extraocular movements, papilledema, or restriction of visual fields (especially bitemporal hemianopia); all suggestive of pituitary tumor. Breasts should be evaluated for gynecomastia (see later discussion). Gynecomastia is more common in men with primary hypogonadism, because of the fact that elevated LH levels stimulate synthesis of estradiol by the testes, resulting in increased ductal tissue in the breast. Squeezing of the nipple may elicit galactorrhea, which, although rare in males, is highly suggestive of a prolactinoma.
|
FIGURE 85.3. Prader orchidometer. The beads of various sizes represent testicular volume. |
Examination of the genitals is critical. Pubic hair pattern should extend up the linea alba to the umbilicus in a diamond shaped pattern (the so-called male escutcheon). A triangular pattern cut off at the pubis suggests androgen deficiency, as does sparse or excessively fine pubic hair. Penile size and location of the urethral meatus, scrotal rugosity and pigmentation, and size and turgor of the testicles should all be noted. The normal adult testis should be 20 to 25 mL in volume (approximately 7.0 × 4.0 cm). The testicular volume can be measured by use of a Prader Orchidometer (Fig. 85.3). On palpation the testes should have the resistance of a firm plum. An “overripe,” softer feeling is a sign of testicular atrophy. Small and firm testes are present in Klinefelter syndrome. Palpation of the left side of the scrotum while the patient performs a Valsalva maneuver may reveal the presence of a varicocele, which is almost always on the left side (venous drainage from the left testis crosses over to the right). Approximately 5% of varicoceles are associated with reduced testosterone production from both testes. Rectal examination should assess prostate size since the prostate shrinks with testosterone deficiency. Careful neurologic examination should include testing the sense of smell to look for Kallmann syndrome.
Laboratory Evaluation
Male hypogonadism is a clinical diagnosis that should be confirmed with laboratory tests. The clinician should measure testosterone only when hypogonadism is suspected based on history and physical examination. Testosterone should not be measured in a hospitalized patient since any acute illness may result in decreased testosterone
P.1459
production (discussed later). Ninety-five percent of healthy young adult men have morning serum testosterone levels of 300 to 1,000 ng/dL (with most between 450 to 700 ng/dL). Since testosterone levels peak in the morning and diurnal variation in testosterone concentration can produce an afternoon or evening decrement of as much as 200 ng/dL, it should be checked at 8 a.m. Early morning values <300 nanograms per deciliter (confirmed twice) in a symptomatic man are considered hypogonadal. Total serum testosterone is generally reliable in most patients and should be the first screening test. If a low total testosterone level is confirmed, the next step is to determine whether it is primary or secondary by measuring LH and FSH. Different assays for LH and FSH have different ranges of normal values. Elevated gonadotropins and low testosterone levels indicate primary gonadal failure. Further workup should be directed to determine the etiology of testicular dysfunction. Karyotyping can be performed to diagnose Klinefelter syndrome. High gonadotropins and normal testosterone levels may also be seen in evolving primary hypogonadism, especially that associated with age, when an increase in pituitary gonadotropin secretion is required to compensate for the testicular failure. To the contrary, low or inappropriately normal gonadotropins in the presence of a subnormal testosterone level indicate secondary hypogonadism. Fasting prolactin should be measured since hyperprolactinemia of any etiology results in secondary hypogonadism by inhibiting GnRH synthesis. All men with tests indicative of secondary hypogonadism should undergo MRI of the pituitary to evaluate for mass lesions. Iron studies should be performed in both forms of hypogonadism since hemochromatosis may involve both the pituitary and the testes.
Although total testosterone measurement is generally accurate, it is affected by variations in plasma SHBG, which may increase with aging and decrease with obesity and liver disease. If the patient is obese and total testosterone levels are repeatedly in the borderline range, it may be helpful to obtain unbound (free) or bioavailable testosterone. Similarly, if an elderly man has borderline normal total testosterone levels but continues to have classic symptoms of hypogonadism, unbound or bioavailable testosterone should be obtained. The unbound testosterone always should be measured by the equilibrium dialysis method and this should be indicated on the request form. Analog and radioimmunoassay methods for direct measurement of unbound testosterone are unreliable and should not be used.
Men with androgen receptor mutations (resistance to testosterone action) present with normal or increased testosterone levels. Gonadotropins may be normal or elevated. Because, as noted earlier, these patients present with ambiguous genitalia at birth, they rarely present as a diagnostic problem for the primary care clinician. Figure 85.4 provides a general algorithm for the evaluation of men with hypogonadism.
|
FIGURE 85.4. Algorithm for evaluation of male hypogonadism. |
Hypogonadism Associated with Chronic Disease
It is now recognized that a variety of acute and chronic illnesses are often associated with male hypogonadism. A severe acute illness results in a dramatic decline in serum testosterone levels. The etiology is multifactorial and is probably due to a combination of hypothalamic stress, anesthesia (when administered), and starvation. In most situations, the mechanism is central hypogonadism, suggested by the observation that serum gonadotropin levels decline even in postmenopausal women (in whom the levels are elevated) admitted to intensive care units, particularly if there has been weight loss (23).
Before the widespread use of highly active antiretroviral treatment, nearly one third of men infected with the human immunodeficiency virus (HIV) were found to be hypogonadal (24). Similar observations have been made in men with other chronic diseases, such as cancer, heart disease, renal failure, and diabetes mellitus (25,26). Investigations are ongoing to determine whether testosterone therapy would be beneficial in these disease states. There is evidence that HIV-infected men increase their weight, lean body mass, and muscle strength after 3 months of testosterone administration (27,28). It is not clear, however,
P.1460
whether these changes result in increased survival or decreased morbidity.
Treatment
Virilization or Fertility
Once the underlying etiology is addressed, the next question is the specific treatment for hypogonadism. If the patient is interested only in virilization and not in fertility, the aim of therapy is adequate androgen replacement (29). The reasons for replacing testosterone in male hypogonadism are multiple. The most pressing reason is to ameliorate or reverse the symptoms of testosterone deficiency (e.g., hot flashes, decreased libido, erectile dysfunction, emotional lability) and to restore male secondary sex characteristics (e.g., beard growth, pubic hair). Beyond this, testosterone deficiency in adults is associated with loss of lean body mass and muscle strength (30), reduced bone mineral density (i.e., osteoporosis) (15), and an increase in percent body fat with greater central fat distribution. Testosterone replacement can improve or reverse the hypogonadal changes in body composition and function (31,32). Hypogonadism is also accompanied by an adverse lipid profile (increased low-density lipoprotein cholesterol and triglyceride), insulin resistance, and metabolic syndrome (33) (see Chapter 79).
In contrast, an alternative approach is required if fertility induction is desired (see later discussion).
Treatment of Specific Causes
Prolactinomas
The primary therapy of all prolactinomas (micro and macro) is medical. Treatment with the synthetic dopamine agonists bromocriptine or cabergoline normalize (or lower) serum prolactin (34, 35, 36), resulting in restoration of testosterone levels, improving libido, shrinking tumor mass, and improving vision. (See Chapter 81 for additional details.)
Hemochromatosis
Hemochromatosis is an underappreciated cause of male hypogonadism, both primary and secondary. Excess iron may be deposited in both the testes and the pituitary (where it has the highest affinity for the gonadotropes). It is important to consider hemochromatosis in the differential diagnosis of male hypogonadism since therapeutic phlebotomy has resulted in normalization of testosterone levels.
Pituitary Adenomas
Central hypogonadism can be caused by a secretory pituitary tumor (prolactinoma or Cushing syndrome) or a nonsecretory adenoma (a macroadenoma that affects production of testosterone by compressing gonadotropes). An imaging procedure, usually magnetic resonance imaging with gadolinium, can detect a mass affecting the hypothalamus, the pituitary stalk, or the pituitary gland. Surgery is performed for functional adenomas (except prolactinomas) and for macroadenomas causing hypopituitarism or visual disturbance. In some cases postoperative radiation therapy is required. (See also Chapter 81.)
Testosterone Replacement Therapy
Options for testosterone replacement include intramuscular esters, transdermal patches or gels, and buccal testosterone. Oral anabolic agents (e.g., oxandrolone, nandrolone, oxymetholone) are not suitable for androgen replacement and should not be used. In Europe and Australia, respectively, oral testosterone undecanoate and testosterone pellets are used. However, these agents are not available in the United States.
Intramuscular Esters
The traditional method of testosterone replacement is injection of testosterone esters such as enanthate, cypionate, or other esters in oil. Esterification of native testosterone makes it more lipophilic. After intramuscular injection, testosterone is gradually released from its oil-based vehicle, prolonging its duration of action. Effective therapy requires injections at regular intervals. Therapy is usually started at a dose of 200 mg every 2 weeks. Although this form of therapy does provide end-organ benefits, injections result in supraphysiological testosterone levels immediately after the dose that may fall to hypogonadal levels before the next injection (depending on the dose and interval). These “roller-coaster” pharmacokinetics result in fluctuation in mood, energy, and libido. Another limitation is that the injections are painful and necessitate regular visits to the caregiver's office or clinic (unless the patient or his family members learn to inject). The advantage of this approach is that it is the cheapest form of testosterone replacement. To judge adequacy of replacement, testosterone levels should be measured at the midpoint between injections (e.g., if injections are administered every 2 weeks, testosterone should be checked at the end of the first week).
Transdermal Testosterone
Testosterone patches are effective at mimicking the normal circadian rhythm (because of slow release of testosterone) and at relieving hypogonadal symptoms. The 5-mg Androderm patch results in peak serum testosterone levels 12 hours after application and can be applied to any skin surface that does not have underlying bony projections (e.g., back, thigh, chest, buttocks). Although the patch adheres fairly well, some men develop skin irritation and, occasionally, severe skin reactions. These reactions are
P.1461
because of permeation-enhancing chemicals in the patch that increase transdermal absorption of testosterone. Such reactions can be prevented by use of 1% triamcinolone ointment before application of Androderm.
A related form of testosterone replacement therapy is transdermal gel. AndroGel 1%, which is available in 2.5- and 5-g packets, was the first gel approved. This clear gel is alcohol-based and is rubbed on the upper arms, back, and abdomen every morning. The gel dries within 10 minutes and the hormone is stored under the skin and slowly diffuses into the circulation over 24 hours. It is advisable not to shower or swim for 4 hours postapplication. Because there can be transference of gel within a few hours of application, direct skin contact with others (including sexual activity) should be avoided for at least 4 hours. The dose of 5 g results in mean serum testosterone levels of approximately 500 to 600 ng/dL. A second gel, Testim, was recently approved in the United States. It is available in 5- and 10-g tubes and has the same pharmacokinetic profile as AndroGel. These gels are well tolerated with little or no skin irritation, but are more expensive than the other forms of replacement.
Buccal Testosterone
Striant, the first buccal testosterone, was recently approved in the United States. Each buccal tablet is 30 mg and is applied twice daily (37). It is applied to the depression in the gum above the upper incisors. Testosterone is absorbed through the buccal mucosa directly into the systemic circulation. Adverse effects include bad taste and problems with adherence. Some subjects have accidentally swallowed the tablet.
Table 85.2 summarizes the various modalities of testosterone replacement.
Fertility
For patients who desire fertility, testosterone replacement alone is not sufficient. Patients with hypogonadism may or may not be infertile, depending on the underlying etiology. Infertility that is primarily testicular is usually resistant to medical intervention and sperm production cannot be induced because of damaged seminiferous tubules. Moreover, testosterone replacement suppresses LH and FSH, causing further reduction in sperm counts and testicular size. Testicular biopsy might be needed in some patients to isolate spermatozoa for procedures such as in vitro fertilization and intra-cytoplasmic sperm insemination. In contrast, in patients with central hypogonadism (i.e., LH or FSH deficiency), infertility as well as deficient testosterone levels may be treated with gonadotropins. Human chorionic gonadotropin (hCG) may be used for its LH-like activity (since human LH is unavailable). Injections of 2000 IU of hCG intramuscularly three times weekly normalize testosterone levels, usually within a few months after initiation of therapy, and may also stimulate spermatogenesis. In patients with a history of cryptorchidism or prepubertal onset of central hypogonadism, both hCG and FSH may be required to initiate spermatogenesis. The dose of FSH is 75 to 150 units intramuscularly three times weekly administered with hCG. Because of the requirement for more frequent injections compared with testosterone, and their expense, use of gonadotropin injections probably should be restricted to those patients with central hypogonadism who are concerned about fertility.
|
TABLE 85.2 Testosterone Replacement Therapies Available in the United States |
|||||||||||||||||||||||||||||||||
|
Adverse Effects of Testosterone Replacement
Generally, testosterone replacement is a safe and effective treatment for male hypogonadism. Although testosterone therapy does not induce prostate cancer, it potentially can promote the growth of a microscopic focus of an existing cancer. The higher prevalence of prostate cancer with older age necessitates that prostate-specific antigen (PSA) be measured and a digital rectal examination (DRE) be done before initiation of therapy in all men older than 50 years of age (see Followup Strategy, below). Testosterone is a known stimulator of erythropoietin and testosterone replacement carries the risk of erythrocytosis. Patients with existing risk factors for erythrocytosis such as hypoxemic lung disease or smoking may be more vulnerable. Hematocrit values should be monitored periodically, initially after 3 months and then annually. There are no definitive data to suggest that physiologic testosterone replacement alters glucose tolerance. A recent study showed that hypogonadism is associated with an adverse lipid profile and that testosterone replacement results in significant lowering of total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, while causing no significant change in serum high-density liporprotein (HDL) levels (38).
Followup for Men on Testosterone Replacement Therapy
Followup of treated patients should include questions about efficacy and adverse effects. Questions should be
P.1462
asked about sexual function and there should be an assessment of body habitus, beard growth, and in patients with failure of pubertal development, growth in stature, growth of phallus, and depth of voice. Libido and potency usually return within a few weeks after initiation of treatment, whereas secondary sex characteristics improve gradually after 6 to 12 months. The patient should be evaluated for gynecomastia or prostate enlargement (e.g., symptoms of urinary hesitancy and frequency). Hematocrit levels should be measured every 3 to 6 months, and the dose of testosterone should be reduced if the hematocrit rises to more than 54%. PSA should be checked quarterly in the first year and then annually. If PSA increases to >4 ng/mL or rises at a rate of 0.75 ng/ml/year, androgen therapy should be discontinued and a referral to a urologist should be made (39,40).
Andropause
Testosterone levels in men begin to decline in the fourth decade of life. This decline is gradual and occurs at the rate of 110 ng/dl/decade (41). At the same time, SHBG levels increase, resulting in a steeper decrease in free and bioavailable testosterone. This decline was observed even in studies in which older men were carefully selected to match younger men in terms of health, obesity, alcohol intake, and social class (42). In the Baltimore Longitudinal Study of Aging, low levels of total testosterone occurred in 19%, 28%, and 49%, respectively, of men in their sixties, seventies, and eighties, whereas the corresponding prevalence of reduced free testosterone levels were 34%, 68%, and 91% (43). Although “male menopause” is a poor choice of words, andropause is a more appropriate term, referring to age-related reductions in the production of testosterone. While the timing of menopause in women is usually obvious because it is associated with the cessation of menses, the signs and symptoms of andropause are often subtle and nonspecific, and they do not occur in all men nor do all aging men experience a significant decline in androgen levels (44).
Andropause occurs due to age-related derangements at all levels of the HPG axis. The decline in androgens is generally accompanied by an increase in circulating estrone and estradiol. In the majority of the cases, gonadotropins remain in the normal range. There is a decline in the number of Leydig cells in the testes with aging, and the testes do not respond as robustly to HCG in aging men as they do in young men (45,46). Similarly, there is decreased GnRH production or release from the hypothalamus with aging, suggesting a decrease in activity of the GnRH pulse generator (47).
The clinical significance of andropause remains controversial. Independent of changes in levels of sex steroids, studies in healthy men revealed a steady decrease in sexual interest and ability, with decreases in the frequency of intercourse from an average of two to three events a week to fewer than two a month by age 70 to 75 years (48). This decrease does not appear to be directly related to hypogonadism but probably reflects changes in other systems (i.e., nervous and vascular) that occur with age. Although testosterone treatment may result in improvement in libido in men with hypogonadism, erectile function generally does not improve in elderly men, since they commonly have comorbidities that complicate the mechanism of the sexual function.
Testosterone administration has been shown to improve body composition, with increases in muscle mass and decreases in body fat, in aged andropausal men (49), as it does in frankly hypogonadal young and middle-aged men (32). Whether the increase in muscle mass is associated with improved functional status or with decreased morbidity or mortality remains to be determined. Testosterone supplementation of healthy aged men with low serum testosterone levels also increases lumbosacral spine bone mineral density (50), and improves visuospatial performance and verbal memory (51). Epidemiologic studies suggest that the decline in free testosterone index is associated with an increase in the incidence of Alzheimer disease (52), and that higher bioavailable testosterone concentrations are associated with better long-term verbal memory (53).
There are no data to support a beneficial effect of administration of androgens to aging men whose testosterone levels are normal. Since there are no clear guidelines for routine screening of elderly men, testosterone levels should be checked only if a patient has symptoms suggestive of hypogonadism or has osteopenia or osteoporosis on bone densitometry. Testosterone levels should not be checked simply to know what they are in an asymptomatic, healthy man. The benefits and risks of androgen replacement in andropausal men remain to be determined conclusively. In the meantime, many endocrinologists consider low libido (but not erectile dysfunction) and decreased spinal bone density to be the only indications for androgen replacement in elderly men.
Gynecomastia
Gynecomastia refers to the benign enlargement of the male breast. It occurs as a result of ductal proliferation of the breast tissue and is usually present beneath the areola. It should be distinguished from “pseudogynecomastia,” which is simply adipose tissue enlargement seen in obese men. Enlargement of the male breast requires a clinician's attention so that those cases with a serious hormonal or neoplastic cause can be distinguished from the common benign idiopathic forms.
P.1463
Etiology
There are three physiologic forms of gynecomastia (54). The first occurs after birth and it is due to the influence of maternal estrogens on the fetus. This regresses in a few months. Gynecomastia also occurs during puberty as plasma sex steroid hormone levels rise (occurring in up to 65% of boys at the age of 14 years). This is caused by increased testosterone secretion, resulting in increased formation of estradiol. However, breast enlargement regresses spontaneously in most and is present in fewer than 15% of boys by age 17 years. The prevalence of gynecomastia again increases to approximately 60% in men 50 years of age and older. The reason for this gynecomastia of senescence is an increased estrogen/testosterone ratio (because of declining androgen production and steady levels of estradiol). Mild idiopathic gynecomastia is almost always less than 5 cm in diameter and causes no symptoms. Noticeable gynecomastia of greater than 5 cm in diameter may be the first clue to the presence of a benign or malignant adrenal or testicular neoplasm or a prolactinoma. Hypogonadism, especially primary hypogonadism, may present with gynecomastia. Malignancies of the testis, lung, stomach, and occasionally other cancers may secrete hCG, which may overstimulate testicular androgen production, leading to gynecomastia. Hyperthyroidism also has been associated with breast enlargement. Ingestion of exogenous estrogen (e.g., by individuals with gender dysphoria or prostate carcinoma) or of antiandrogenic drugs such as cimetidine, spironolactone, digoxin, and ketoconazole may cause male breast enlargement. Many other medications have been reported to be associated with gynecomastia, but the causal relationship is less well established. Gynecomastia is also common in liver cirrhosis, in which hepatic metabolism of estrogens is impaired. Approximately 1% of all breast carcinomas occur in men. If a man presents with an eccentric breast mass, nipple retraction, or reddish discharge, one should suspect breast cancer. Table 85.3summarizes the various causes of gynecomastia.
Diagnosis
History
The duration and age at onset of breast enlargement are important; for example, recent onset of breast swelling in a 30-year-old man would be of more concern than in an adolescent or gradual breast enlargement in a 70-year-old man. The presence of tenderness or discharge and the quality of the discharge (clear, turbid, bloody) should be noted. Any symptoms of hypogonadism (see previous discussion) should be elicited, as should symptoms of hyperthyroidism. A careful medication history and sexual history may reveal an exogenous cause.
|
TABLE 85.3 Causes of Gynecomastia |
||||||||||||||||||||
|
Physical Examination
Generally, the examination should be the same as for hypogonadism (described earlier), and signs of thyroid disease should be emphasized. Deep palpation of the upper abdomen may reveal an adrenal tumor or downward displacement of the kidney by such a tumor. Careful bimanual palpation of the testicles may detect a tumor. A system for staging breast development was described by Marshall and Tanner in adolescent girls (see Chapter 11), but it is equally useful for staging gynecomastia. The examiner needs to differentiate between proliferation of glandular breast tissue (firm, slightly lobulated, and symmetrically distributed from the nipple outward with a limited boundary), fat (softer, diffusely distributed, and with no clear separation from surrounding subcutaneous adipose tissue), and tumor (hard, nodular, frequently tender, often fixed to skin or underlying muscle, and eccentrically located with regard to the nipple). Milky nipple discharge on firm squeezing suggests prolactinoma; clear or bloody discharge suggests breast cancer. Unilateral breast enlargement should increase the suspicion of neoplasia, but asymmetry occurs in 10% to 15% of patients with idiopathic gynecomastia. Whether further investigation is required depends on the age of the patient, the rapidity of
P.1464
enlargement of the breast, and the degree of such enlargement. Men between 18 and 45 years of age with recent onset of rapidly enlarging mammary glands, or with glandular breast tissue diameter greater than 5 cm, or with symptoms or signs suggesting hypogonadism or hyperthyroidism should receive further evaluation.
Laboratory Evaluation and Diagnosis
Determinations of serum levels of estradiol, testosterone, gonadotropins (LH and FSH), prolactin, hCG-β, TSH, and free T4 are indicated. If the serum estradiol is greater than 50 pg/mL and if the testosterone/estradiol ratio is reduced to less than 100:1, the diagnosis of estrogen-secreting testicular tumor is strongly suggested. This should lead a primary care practitioner to obtain a testicular ultrasound. Low or low-normal testosterone levels with increased FSH and LH in late adolescent or young adult males with gynecomastia and testicular atrophy (small, firm testes) suggest the diagnosis of Klinefelter syndrome (47,XXY). Elevated serum hCG should prompt a search for occult malignancy with particular attention to gonads, lungs, and gastrointestinal (GI) tract. Elevated prolactin concentrations may be associated with the use of certain medications (e.g., antipsychotic drugs) or with a prolactinoma (see Chapter 81). Elevated free T4 and low TSH determinations suggest hyperthyroidism as the cause of gynecomastia. If the above tests are inconclusive, 24-hour urinary 17-ketosteroids should be measured. Elevated levels indicate an adrenal cause of gynecomastia, in which case adrenal hyperfunction should be investigated with the diagnosis of adrenal neoplasm in mind (see Chapter 81).
Imaging
Patients with firm, nodular, unilateral, or notably eccentric breast enlargement should be referred for mammography, ultrasound, or surgical biopsy of the breast.
Treatment
No treatment is needed for physiologic causes of gynecomastia since it remits spontaneously. Similarly, drug-induced gynecomastia remits gradually, in several months, after the drug is discontinued. Treatment of a primary endocrine disease (e.g., prolactinoma, hyperthyroidism, or hypogonadism) should be guided by an endocrinologist. Remission of the accompanying gynecomastia depends on the success of the treatment and the stage of advancement of breast development. Estrogen receptor antagonists such as tamoxifen and aromatase inhibitors have shown some success in the treatment of gynecomastia (55,56). If idiopathic gynecomastia is a cosmetic problem, liposuction or surgical excision of breast tissue may be attempted. Breast development that has progressed to the fibrotic stage will never regress fully, even if the cause is corrected, and therefore will require surgical intervention if complete cosmetic correction is desired.
Erectile Dysfunction
In this section, erectile disorder (ED) and loss of libido are considered only as they relate to endocrine disorders. For a more general discussion of sexual dysfunction, see Chapter 6. ED, sometimes referred to as impotence, is the inability to achieve or maintain erection satisfactorily enough to achieve penetration and ejaculation. Transient or occasional ED is common and is not necessarily evidence of a medical problem, but a pattern of repeated episodes (more than 25% of opportunities) lasting longer than 1 month should be investigated. ED may or may not be accompanied by loss of libido, depending on the cause.
Etiology
A disorder of any of the systems that maintain the sexual response may lead to erectile dysfunction. Causes may therefore be of several types: (a) psychological; (b) vascular, either of the arterial type, with diminished blood supply to the corpora cavernosa (e.g., congenital vascular anomaly, traumatic injury to vessels, large vessel atherosclerosis, disease of smaller peripheral vessels), or as a result of venous incompetence, in which partial erections occur but blood drains off because of “venous leak;” (c) neuropathic, involving damage to the peripheral pelvic autonomic nerves (e.g., diabetic neuropathy, heavy metal poisoning, nerve trauma) or disease of the spinal cord or brain (e.g., tumor, multiple sclerosis) that inhibits or obliterates the erectile response; (d) toxic, caused by substances of abuse (e.g., alcohol, opiates, sedatives) that can acutely and chronically diminish sexual ability or by a number of medications that affect the autonomic and central nervous system (e.g., antipsychotic drugs, sympatholytic antihypertensives); (e) debilitative, related to various severe and chronic medical illnesses (e.g., malignancy, renal failure, cachexia of any etiology) that are accompanied by loss of sex drive; and (f) endocrine, including hypogonadism and prolactinoma (see earlier discussions), hyperthyroidism and hypothyroidism, Cushing syndrome, and acromegaly. In one series of patients referred to a major diagnostic center for persistent symptoms, 35% were found to have an endocrine disorder (57).
Diagnosis
History
It is important to differentiate various aspects of sexual dysfunction. These include decreased libido (desire to have sex), erectile dysfunction (inability to attain and maintain
P.1465
erection during intercourse), and premature ejaculation (ejaculation of semen prior to achieving orgasm or intending to achieve it). The duration of symptoms, the frequency with which intercourse is attempted, and the proportion of attempts ending in erectile failure should be ascertained to determine whether the ED is absolute or relative and whether it is progressing. Rapid onset of ED usually indicates psychogenic impotence or genitourinary trauma (e.g., prostate surgery). Partial or nonsustained erections are suggestive of anxiety whereas absolute loss of erections indicates a neurologic or vascular disorder. Erectile dysfunction unaccompanied by loss of libido suggests a neurologic or vascular problem, whereas loss of libido is consistent with either hypogonadism or a psychological cause. The history should include the patient's marital situation, whether there are sex partners other than the spouse, the perceived level of partners’ desire, and a social and work history to determine whether there are psychosocial stressors. Situational ED (i.e., experienced with one partner but not another) is also good evidence of a psychological problem. Men are often awakened in the morning with an erection. This is a normal response to a full bladder, with spontaneous detumescence following urination. Preservation of morning erections is good evidence against endocrine, vascular, or neuropathic disease; however, 14% of patients with an endocrine problem maintain morning erections (57). A history of medication use and substance abuse should be sought. Heavy smoking is often associated with a peripheral vascular cause of impotence. The patient should be asked about symptoms of hypothyroidism, hyperthyroidism, Cushing disease, diabetes, peripheral neuropathy (paraesthesia, hyperesthesia), or CNS disease and vascular disease (claudication, angina, cold extremities, skin ulcers). Pain during intercourse or the presence of a curved penile shaft suggests Peyronie disease.
Physical Examination
The physical examination should be conducted with particular attention to the manifestations of hypogonadism described earlier, signs of thyroid or adrenal disease (see Chapters 80 and 81), signs of peripheral vascular disease (peripheral pulses, skin temperature, skin atrophy, hair loss; see Chapter 94) and central or peripheral neuropathy (see Chapter 92). The penile shaft should be palpated to determine whether plaques of Peyronie disease are present. These are fibrous bands within the tunica albuginea that may involve the full length of the penile shaft.
Laboratory Evaluation
Hormone levels should be measured to screen for hypogonadism (serum total testosterone drawn at 8 a.m.) and for a prolactinoma (fasting serum prolactin) (see earlier discussion). If historical or physical findings lead to suspicion of thyroid or adrenal disease, appropriate tests should be done (see Chapters 80 and 81). A fasting blood glucose measurement should always be obtained to screen for diabetes mellitus (see Chapter 79).
Additional Testing
Spontaneous erection during sleep, or nocturnal penile tumescence, had been thought to exclude organic etiologies of ED, but that criterion is not completely valid, since some erectile function may be preserved early in organic disease. Many experts and consensus guidelines now emphasize the importance of the history and physical examination in evaluating erectile dysfunction and do not recommend routine testing for nocturnal penile tumescence. If a test is done, it can sometimes be done at home.
The “stamp test” is a simple but unvalidated procedure in which a man fastens a strip of perforated postal stamps around his penis by moistening the overlapping stamp in the usual manner; separation of the stamps at the perforations overnight is considered evidence of erection. Calibrated “snap gauges,” which consist of plastic bands of varying strength, and “strain gauges,” which include elastic bands that stretch and register changes in circumference, are commercially available.
In selected patients in whom more detailed assessment of the capacity for erection is sought, specialized testing may be undertaken, usually under the direction of a urologist. Electronic monitoring devices are available for home use, and quantitative instrumentation in a sleep laboratory may also be obtained. Definitive diagnosis of vascular disorders may require Doppler studies of penile blood flow or selective angiography, and venous incompetence may be revealed by dynamic cavernosography, procedures used by urologists specializing in ED. If peripheral neuropathy seems a likely cause, it often can be confirmed by referral to a urologist for bladder manometrics and to a neurologist for nerve conduction velocity measurements (see Chapter 92).
Treatment
Therapeutic efforts should be directed at the specific cause of the ED. Psychogenic ED may respond to various therapeutic modalities depending on its severity and associated problems (see Chapter 6). Vascular disease may respond to medication or to surgical revascularization. Caution should be exercised in this regard since, in contrast to young men, results are almost always disappointing in older patients with atherosclerotic disease (perhaps because of the involvement of smaller peripheral vessels). Neuropathic ED is occasionally reversible with removal of an inciting lesion (e.g., spinal cord tumor) or with aggressive diabetic control, but, if irreversible, it may also be treated with other measures (discussed below). Drug-induced ED is usually reversed if the offending agent can be discontinued. Treatment of hypogonadism has been
P.1466
discussed above. If sexual function does not improve within 6 weeks after specific therapy for an organic cause has been instituted, consideration should be given to the possibility that the experience and expectation of sexual failure are inhibiting the response (so-called performance anxiety) even though the primary cause is no longer present. Such secondary psychological ED may respond to psychological or behavioral therapy (see Chapter 6).
Advances in pharmacotherapy have resulted in newer approaches that may succeed in restoring sexual function in a variety of conditions (psychogenic, organic, or multifactorial). Three selective inhibitors of cyclic guanosine monophosphate–specific phosphodiesterase type 5 are currently available. The inhibition of this enzyme leads to increased concentrations of nitric oxide, resulting in vasodilatation and increased genital blood flow. These agents are taken orally. The first drug in this class was sildenafil citrate (Viagra). Doses of 50 to 100 mg are taken 1 hour before planned sexual activity. The second agent that became available was vardenafil (Levitra) that is taken in doses of 10 to 20 mg 1 hour before sexual activity. Both sildenafil and vardenafil are effective for up to 4 hours. The latest drug in this class is tadalafil (Cialis). This drug has the same onset of action, but it has a duration of action of 36 hours. All three drugs have equal efficacy of approximately 60% to 75%. Although these drugs have similar side effects of headaches and dyspepsia, sildenafil results in transient bluish vision in a minority of patients due to cross-reactivity with retinal phosphodiesterase. A few cases of acute loss of vision secondary to ischemic optic neuropathy have been reported among men who took sildenafil. However, this was a rare occurrence and a causal relationship to the phosphodiesterase inhibitors has not been established conclusively (58). The absorption of sildenafil and vardenafil is inhibited by foods with a high fat content, but there are no such interactions with tadalafil. All three drugs are contraindicated in men taking nitroglycerin and nitrate medications.
For patients who cannot take phosphodiesterase type 5 inhibitors, injection of vasoactive agents directly into the corpus cavernosum is the next step. Most effective are prostaglandin E1 (PGE1, alprostadil) or papaverine combined with phentolamine. Both treatments are equally effective, but papaverine plus phentolamine use is associated with a lower frequency of priapism and pain (59). These drugs are injected 15 minutes prior to sexual activity and their effects last for 1 hour. Injection therapy should always be supervised by an experienced urologist, because priapism is a potentially serious (2% to 4%) acute complication. A rare long-term complication is gradual fibrosis of the corpora cavernosa with loss of responsiveness. Alprostadil administered as a urethral suppository (available as MUSE or medicated urethral system for erection, provided in doses of 125 µg, 250 µg, 500 µg, and 1,000 µg) is another approach to the treatment of ED. The efficacy and adverse reaction rates of urethral alprostadil appear to be comparable to those of injection therapy (60,61), but experience with this method is still relatively limited. Furthermore, it should not be used if the partner is pregnant.
Still another option is the use of a vacuum device that draws blood into the penis by negative pressure; an occlusive ring applied to the base of the penis maintains the erection. Several different types of suction devices are available. Results with these devices are mixed. For example, one retrospective study found that 81% of men using vacuum devices abandoned them because they “did not work,” and the patients’ attitudes toward the device were unfavorable overall (62). Another study, however, showed that more than 80% of the men achieved satisfactory erections with vacuum devices (63).
The final option is a penile prosthesis. Implantable penile prostheses have been used extensively but, because of local complications, are no longer as popular as they once were. Implants are available in two basic types: those that are permanently stiff or semiflexible, and more complex devices that inflate by means of a pump and valve mechanism. Complications are related to surgery and wound infections. Implants should be the last modality considered by men with ED, in consultation with a urologist.
Specific References
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
P.1467